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Hidradenitis Suppurativa: Host-Microbe and Immune Pathogenesis Underlie Important Future Directions

  • Simon W. Jiang
    Affiliations
    Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
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  • Melodi Javid Whitley
    Affiliations
    Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
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  • Paula Mariottoni
    Affiliations
    Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
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  • Tarannum Jaleel
    Affiliations
    Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
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  • Amanda S. MacLeod
    Correspondence
    Correspondence: Amanda S. MacLeod, Department of Dermatology, Duke University, 40 Duke Medicine Circle, DUMC3135, Durham, NC 27710, USA.
    Affiliations
    Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA

    Pinnell Center for Investigative Dermatology, Duke University School of Medicine, Durham, North Carolina, USA

    Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA

    Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA

    Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA

    Duke Microbiome Center, Duke University Medical Center, Durham, North Carolina, USA
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Open AccessPublished:January 11, 2021DOI:https://doi.org/10.1016/j.xjidi.2021.100001
      Hidradenitis suppurativa (HS) is an inflammatory disease of the skin with a chronic, relapsing-remitting course. The pathogenesis of the disease is poorly understood and involves multiple factors, including genetics, environment, host-microbe interactions, and immune dysregulation. In particular, the composition of the cutaneous microbiome shifts as the disease progresses, although it is unclear whether this is a primary or secondary process. Trials with immunomodulatory therapy elucidate the role of specific immune pathways and cytokine signaling in disease mechanism, such as TNF-α, IL-1β, IL-12, IL-17, IL-23, and complement. Future studies should continue examining the causes of and contributing factors to microbial changes and immune dysregulation in HS pathogenesis.

      Abbreviations:

      AMP (antimicrobial peptide), BD (β-defensin), BMI (body mass index), DC (dendritic cell), DCD (dermcidin), GSC (γ-secretase complex), HiSCR (hidradenitis suppurativa clinical response), HS (hidradenitis suppurativa), IBD (inflammatory bowel disease), IHS4 (International Hidradenitis Suppurativa Severity Score System), iNOS (inducible nitric oxide synthase), KC (keratinocyte), MMP (matrix metalloproteinase), NET (neutrophil extracellular traps), NMSC (nonmelanoma skin cancer), pDC (plasmacytoid dendritic cell), PG (pyoderma gangrenosum), RCT (randomized controlled trial), SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis), Th (T helper type), TLR (toll-like receptor)

      Introduction

      Hidradenitis suppurativa (HS, also called acne inversa) is a chronic inflammatory disorder of the skin. The disease is characterized by painful nodules and abscesses in areas with high hair follicle and sweat gland density, such as the axilla and groin (
      • Coates M.
      • Mariottoni P.
      • Corcoran D.L.
      • Kirshner H.F.
      • Jaleel T.
      • Brown D.A.
      • et al.
      The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
      ). These debilitating features can significantly impair QOL and cause psychosocial distress, increasing risk of mood disorders and completed suicide (
      • Anzaldi L.
      • Perkins J.A.
      • Byrd A.S.
      • Kharrazi H.
      • Okoye G.A.
      Characterizing inpatient hospitalizations for hidradenitis suppurativa in the United States.
      ;
      • Thorlacius L.
      • Cohen A.D.
      • Gislason G.H.
      • Jemec G.B.E.
      • Egeberg A.
      Increased suicide risk in patients with hidradenitis suppurativa.
      ). The prevalence ranges from 0.053% in US studies to as high as 4.1% in European studies, although the latter consisted of relatively small sample sizes (
      • Cosmatos I.
      • Matcho A.
      • Weinstein R.
      • Montgomery M.O.
      • Stang P.
      Analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the United States.
      ;
      • Miller I.M.
      • McAndrew R.J.
      • Hamzavi I.H.
      Prevalence, risk factors, and comorbidities of hidradenitis suppurativa.
      ). The incidence of HS in the US appears to be increasing from 4.3 per 100,000 between 1970 and 1979 to 9.6 per 100,000 from 2000 to 2008 (
      • Vazquez B.G.
      • Alikhan A.
      • Weaver A.L.
      • Wetter D.A.
      • Davis M.D.
      Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota.
      ).
      The pathogenesis of the disease is complex and multifactorial. This review aims to explore the relationships of risk factors, associated conditions, and mechanisms of cutaneous innate immunology and microbe-host interactions. Furthermore, we review current therapies of HS, with particular focus on drug innovations that reveal mechanisms of immunologic pathophysiology.

      Staging

      Multiple scoring systems exist to assess the severity of HS disease. Perhaps the most well-known is the Hurley staging system, which consists of three stages. Briefly, stage I is characterized by abscess formation without scarring or sinus tracts, stage II by recurrent abscess(es) with scarring and sinus tract formation, and stage III by diffuse involvement with interconnected sinus tracts and abscesses spanning an entire area (
      • Hurley H.
      Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus: surgical approach.
      ).
      Various other staging systems exist, including the HS Sartorius score, Physician Global Assessment, and International Hidradenitis Suppurativa Severity Score System (IHS4), among others (
      • Constantinou C.A.
      • Fragoulis G.E.
      • Nikiphorou E.
      Hidradenitis suppurativa: infection, autoimmunity, or both?.
      ). It is important to consider the goals of assessment when choosing which scoring system to employ. HS clinical response (HiSCR) has been used in several clinical trials recently and is defined by at least a 50% reduction in abscess and inflammatory nodule count with no increase in abscess and fistula count compared with baseline (
      • Kimball A.B.
      • Sobell J.M.
      • Zouboulis C.C.
      • Gu Y.
      • Williams D.A.
      • Sundaram M.
      • et al.
      HiSCR (Hidradenitis Suppurativa Clinical Response): a novel clinical endpoint to evaluate therapeutic outcomes in patients with hidradenitis suppurativa from the placebo-controlled portion of a phase 2 adalimumab study.
      ).
      An important potential limitation of using HiSCR to assess clinical efficacy of immunomodulatory therapy is the incomplete understanding of spontaneous progression and remission of disease. Relatively high placebo response rates, sometimes up to 30%, limit interpretation of clinical trial results as there are limited data on placebo-controlled blinded studies (
      • Frew J.W.
      • Hawkes J.E.
      • Krueger J.G.
      Topical, systemic and biologic therapies in hidradenitis suppurativa: pathogenic insights by examining therapeutic mechanisms.
      ). In addition, HiSCR predominantly assesses the more acute changes of HS, whereas chronic changes such as scarring and sinus tracts are not well captured by this metric. Studies with larger cohorts and subgroup analyses are needed to better understand the effects of immunomodulation on HS when employing HiSCR.
      Notably, current staging systems do not account for microbiota composition or dysregulation of immune pathways, which may differ between patients with clinically similar disease. Thus, continued research may augment future staging systems with personalized data regarding each patient’s microbiome and lesional immune profile to choose the optimal personalized treatment regimen.

      Risk Factors and Associations

      Patient characteristics

      Women are more frequently affected by HS, with a female-to-male ratio of 3:1 (
      • Jemec G.B.E.
      Clinical practice. Hidradenitis suppurativa.
      ). Although this disparity may suggest a role for sex hormones in HS pathogenesis, hormone levels of patients with HS appear to lie within normal ranges (
      • Riis P.T.
      • Ring H.C.
      • Themstrup L.
      • Jemec G.B.
      The role of androgens and estrogens in hidradenitis suppurativa - a systematic review.
      ). Symptoms of HS tend to worsen during menses and improve during pregnancy (
      • Vossen A.R.J.V.
      • van Straalen K.R.
      • Prens E.P.
      • van der Zee H.H.
      Menses and pregnancy affect symptoms in hidradenitis suppurativa: a cross-sectional study.
      ).
      HS disease has a notable increased prevalence and more severe symptoms in African American and Hispanic populations (
      • Lee D.E.
      • Clark A.K.
      • Shi V.Y.
      Hidradenitis suppurativa: disease burden and etiology in skin of color.
      ;
      • Vlassova N.
      • Kuhn D.
      • Okoye G.A.
      Hidradenitis suppurativa disproportionately affects African Americans: a single-center retrospective analysis.
      ). Rigorous and in-depth investigations, including genome-wide association studies and genetic and environmental risk assessments, are needed to better understand the reasons for these disparities. Notably, active smokers are 1.9–14.87 times more likely to be diagnosed with HS than nonsmokers (
      • Garg A.
      • Neuren E.
      • Cha D.
      • Kirby J.S.
      • Ingram J.R.
      • Jemec G.B.E.
      • et al.
      Evaluating patients’ unmet needs in hidradenitis suppurativa: results from the Global Survey of Impact and Healthcare Needs (VOICE) project.
      ;
      • Schrader A.M.R.
      • Deckers I.E.
      • van der Zee H.H.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: a retrospective study of 846 Dutch patients to identify factors associated with disease severity.
      ). Former smokers are at a 1.14–1.55 times increased risk of HS (
      • Revuz J.E.
      • Canoui-Poitrine F.
      • Wolkenstein P.
      • Viallette C.
      • Gabison G.
      • Pouget F.
      • et al.
      Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies.
      ;
      • Schrader A.M.R.
      • Deckers I.E.
      • van der Zee H.H.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: a retrospective study of 846 Dutch patients to identify factors associated with disease severity.
      ). Studies have demonstrated an increased risk of Hurley stage II or III disease in smokers compared with nonsmokers with HS (
      • Sartorius K.
      • Emtestam L.
      • Jemec G.B.E.
      • Lapins J.
      Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and obesity.
      ;
      • Schrader A.M.R.
      • Deckers I.E.
      • van der Zee H.H.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: a retrospective study of 846 Dutch patients to identify factors associated with disease severity.
      ;
      • Vazquez B.G.
      • Alikhan A.
      • Weaver A.L.
      • Wetter D.A.
      • Davis M.D.
      Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota.
      ). Smoking is associated with significantly lower rates of disease remission (
      • Kromann C.B.
      • Deckers I.E.
      • Esmann S.
      • Boer J.
      • Prens E.P.
      • Jemec G.B.E.
      Risk factors, clinical course and long-term prognosis in hidradenitis suppurativa: a cross-sectional study.
      ). Patients with obesity (body mass index [BMI] ≥ 30 kg/m2) are 2–6 times more likely to be diagnosed with HS (
      • Gold D.A.
      • Reeder V.J.
      • Mahan M.G.
      • Hamzavi I.H.
      The prevalence of metabolic syndrome in patients with hidradenitis suppurativa.
      ;
      • Sabat R.
      • Chanwangpong A.
      • Schneider-Burrus S.
      • Metternich D.
      • Kokolakis G.
      • Kurek A.
      • et al.
      Increased prevalence of metabolic syndrome in patients with acne inversa.
      ). A study suggested that obesity may contribute to HS severity through proinflammatory cytokine production by adipose cells in addition to contributing to ongoing skin breakdown and maceration in the large skin folds, which can trigger inflammation as well (
      • Miller I.M.
      • McAndrew R.J.
      • Hamzavi I.H.
      Prevalence, risk factors, and comorbidities of hidradenitis suppurativa.
      ).
      There exists an association between metabolic syndrome, a cluster of cardiometabolic conditions including obesity, insulin resistance, hypertension, and lipid abnormalities, and HS (
      • Gold D.A.
      • Reeder V.J.
      • Mahan M.G.
      • Hamzavi I.H.
      The prevalence of metabolic syndrome in patients with hidradenitis suppurativa.
      ;
      • Sabat R.
      • Chanwangpong A.
      • Schneider-Burrus S.
      • Metternich D.
      • Kokolakis G.
      • Kurek A.
      • et al.
      Increased prevalence of metabolic syndrome in patients with acne inversa.
      ). HS is also associated with a significantly increased risk for adverse cardiovascular outcomes and cardiovascular-associated death (
      • Egeberg A.
      • Gislason G.H.
      • Hansen P.R.
      Risk of major adverse cardiovascular events and all-cause mortality in patients with hidradenitis suppurativa.
      ). Mechanistically, the signaling peptide mTOR is persistently elevated in metabolic syndrome (
      • Das A.
      • Reis F.
      • Maejima Y.
      • Cai Z.
      • Ren J.
      mTOR signaling in cardiometabolic disease, cancer, and aging.
      ). Likewise, mTOR is increased in the skin of patients with HS, and its gene expression has been shown to correlate with HS severity (
      • Monfrecola G.
      • Balato A.
      • Caiazzo G.
      • De Vita V.
      • Di Caprio R.
      • Donnarumma M.
      • et al.
      Mammalian target of rapamycin, insulin resistance and hidradenitis suppurativa: a possible metabolic loop.
      ). Adipokines are cytokines secreted by adipose tissue whose levels are altered in metabolic syndrome (
      • Francisco V.
      • Ruiz-Fernández C.
      • Pino J.
      • Mera A.
      • González-Gay M.A.
      • Gómez R.
      • et al.
      Adipokines: linking metabolic syndrome, the immune system, and arthritic diseases.
      ). Two recent studies found decreased levels of the anti-inflammatory adipokine adiponectin and increased levels of the proinflammatory adipokines leptin, resistin, and visfatin in patients with HS (
      • González-López M.A.
      • Vilanova I.
      • Ocejo-Viñals G.
      • Arlegui R.
      • Navarro I.
      • Guiral S.
      • et al.
      Circulating levels of adiponectin, leptin, resistin and visfatin in non-diabetics patients with hidradenitis suppurativa.
      ;
      • Malara A.
      • Hughes R.
      • Jennings L.
      • Sweeney C.M.
      • Lynch M.
      • Awdeh F.
      • et al.
      Adipokines are dysregulated in patients with hidradenitis suppurativa.
      ). Because these studies did not identify an association between adipokine expression and disease severity, more research is needed to understand how adipokines relate to HS susceptibility (
      • González-López M.A.
      • Vilanova I.
      • Ocejo-Viñals G.
      • Arlegui R.
      • Navarro I.
      • Guiral S.
      • et al.
      Circulating levels of adiponectin, leptin, resistin and visfatin in non-diabetics patients with hidradenitis suppurativa.
      ;
      • Malara A.
      • Hughes R.
      • Jennings L.
      • Sweeney C.M.
      • Lynch M.
      • Awdeh F.
      • et al.
      Adipokines are dysregulated in patients with hidradenitis suppurativa.
      ).

      Genetics

      Approximately 34–36% of patients report an affected family member with HS (
      • Canoui-Poitrine F.
      • Le Thuaut A.
      • Revuz J.E.
      • Viallette C.
      • Gabison G.
      • Poli F.
      • et al.
      Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study.
      ). Studies have identified loss-of-function mutations in the PSENEN, NCSTN, and PSEN1 genes, which encode for components of the γ-secretase complex (GSC) (
      • Miskinyte S.
      • Nassif A.
      • Merabtene F.
      • Ungeheuer M.N.
      • Join-Lambert O.
      • Jais J.P.
      • et al.
      Nicastrin mutations in French families with hidradenitis suppurativa.
      ;
      • Pink A.E.
      • Simpson M.A.
      • Desai N.
      • Dafou D.
      • Hills A.
      • Mortimer P.
      • et al.
      Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa).
      ;
      • Wang B.
      • Yang W.
      • Wen W.
      • Sun J.
      • Su B.
      • Liu B.
      • et al.
      Gamma-secretase gene mutations in familial acne inversa.
      ). GSC is an intramembranous protease that targets type I transmembrane proteins for cleavage (
      • Pink A.E.
      • Simpson M.A.
      • Desai N.
      • Dafou D.
      • Hills A.
      • Mortimer P.
      • et al.
      Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa).
      ). An important target of GSC is Notch. The GSC cleaves Notch, resulting in nuclear translocation of the intracellular domain, which affects the expression of factors regulating hair follicle and epidermal cell proliferation (
      • Melnik B.C.
      • Plewig G.
      Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa).
      ). Although impaired Notch signaling is postulated to drive HS pathogenesis, a recent study identified elevated expression of NCSTN, Notch, and their downstream target, PI3K/protein kinase B, in HS lesional skin (
      • Hessam S.
      • Gambichler T.
      • Skrygan M.
      • Scholl L.
      • Sand M.
      • Meyer T.
      • et al.
      Increased expression profile of NCSTN, Notch and PI3K/AKT3 in hidradenitis suppurativa [e-pub ahead of print].
      ). Because GSC mutations are present in only a minority of patients with familial HS, perhaps loss of Notch may only drive HS pathogenesis in this small subset of patients (
      • Liu M.
      • Davis J.W.
      • Idler K.B.
      • Mostafa N.M.
      • Okun M.M.
      • Waring J.F.
      Genetic analysis of NCSTN for potential association with hidradenitis suppurativa in familial and nonfamilial patients.
      ;
      • Pink A.E.
      • Simpson M.A.
      • Desai N.
      • Dafou D.
      • Hills A.
      • Mortimer P.
      • et al.
      Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa).
      ). It is currently unknown which genetic mutations underlie familial HS in patients with absent GSC mutations and how transcriptomic regulation of GSC may affect HS severity (
      • Liu M.
      • Davis J.W.
      • Idler K.B.
      • Mostafa N.M.
      • Okun M.M.
      • Waring J.F.
      Genetic analysis of NCSTN for potential association with hidradenitis suppurativa in familial and nonfamilial patients.
      ;
      • Pink A.E.
      • Simpson M.A.
      • Desai N.
      • Dafou D.
      • Hills A.
      • Mortimer P.
      • et al.
      Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa).
      ).
      Various studies have identified additional genetic contributors to HS. Increased susceptibility to HS is associated with mutations in the TNF gene promoter region and, recently, the MEFV gene (
      • Savva A.
      • Kanni T.
      • Damoraki G.
      • Kotsaki A.
      • Giatrakou S.
      • Grech I.
      • et al.
      Impact of Toll-like receptor-4 and tumour necrosis factor gene polymorphisms in patients with hidradenitis suppurativa.
      ;
      • Vural S.
      • Gündoğdu M.
      • Gökpınar İli E.
      • Durmaz C.D.
      • Vural A.
      • Steinmüller-Magin L.
      • et al.
      Association of pyrin mutations and autoinflammation with complex phenotype hidradenitis suppurativa: a case-control study.
      ). SNPs of the IL12RB1 gene are associated with severity and onset of disease (
      • Giatrakos S.
      • Huse K.
      • Kanni T.
      • Tzanetakou V.
      • Kramer M.
      • Grech I.
      • et al.
      Haplotypes of IL-12Rβ1 impact on the clinical phenotype of hidradenitis suppurativa.
      ). There is an increased prevalence of trisomy 21 in patients with HS, and mean age of HS symptom onset occurs earlier in this patient population (
      • Denny G.
      • Anadkat M.J.
      Hidradenitis suppurativa (HS) and Down syndrome (DS): increased prevalence and a younger age of hidradenitis symptom onset.
      ). More studies are needed to elucidate the major loci of genetic susceptibility to HS.

      Other associations

      HS is associated with various inflammatory diseases (Figure 1). Inflammatory bowel disease (IBD) frequently co-occurs with HS. One study found the prevalence of HS among patients with Crohn disease and ulcerative colitis to be 26% and 18%, respectively (
      • van der Zee H.H.
      • de Winter K.
      • van der Woude C.J.
      • Prens E.P.
      The prevalence of hidradenitis suppurativa in 1093 patients with inflammatory bowel disease.
      ). Pyoderma gangrenosum (PG) is a neutrophil-predominant dermatosis characterized by cutaneous nodules or pustules that rapidly progress to painful deep ulcers. PG has been associated with HS in case reports that describe syndromes consisting of a triad of HS, PG, and acne conglobata with an additional arthritis component (
      • Braun-Falco M.
      • Kovnerystyy O.
      • Lohse P.
      • Ruzicka T.
      Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome.
      ;
      • Leuenberger M.
      • Berner J.
      • Di Lucca J.
      • Fischer L.
      • Kaparos N.
      • Conrad C.
      • et al.
      PASS syndrome: an IL-1-driven autoinflammatory disease.
      ;
      • Marzano A.V.
      • Trevisan V.
      • Gattorno M.
      • Ceccherini I.
      • De Simone C.
      • Crosti C.
      Pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH): a new autoinflammatory syndrome associated with a novel mutation of the PSTPIP1 gene.
      ).
      Figure thumbnail gr1
      Figure 1Risk factors and conditions associated with HS. HS, hidradenitis suppurativa; IBD, inflammatory bowel disease; NMSC, nonmelanocytic skin cancer; PG, pyoderma gangrenosum; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis.
      • Rosner I.A.
      • Burg C.G.
      • Wisnieski J.J.
      • Schacter B.Z.
      • Richter D.E.
      The clinical spectrum of the arthropathy associated with hidradenitis suppurativa and acne conglobata.
      ,
      • Rosner I.A.
      • Richter D.E.
      • Huettner T.L.
      • Kuffner G.H.
      • Wisnieski J.J.
      • Burg C.G.
      Spondyloarthropathy associated with hidradenitis suppurative and acne conglobata.
      established an association between HS and inflammatory arthropathy in two studies, but did not find a correlation with HLA-B27. A dysregulated immune response and microbial triggers may underlie a shared pathophysiology between HS and spondyloarthropathies (
      • Richette P.
      • Molto A.
      • Viguier M.
      • Dawidowicz K.
      • Hayem G.
      • Nassif A.
      • et al.
      Hidradenitis suppurativa associated with spondyloarthritis — results from a multicenter national prospective study.
      ). Another rheumatologic association is synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome (
      • Steinhoff J.P.
      • Cilursu A.
      • Falasca G.F.
      • Guzman L.
      • Reginato A.J.
      A study of musculoskeletal manifestations in 12 patients with SAPHO syndrome.
      ). A case series found that 7 of 12 patients with SAPHO syndrome had evidence of HS (
      • Steinhoff J.P.
      • Cilursu A.
      • Falasca G.F.
      • Guzman L.
      • Reginato A.J.
      A study of musculoskeletal manifestations in 12 patients with SAPHO syndrome.
      ).
      In addition to inflammatory disorders, HS is also associated with conditions in which follicular occlusion underlies pathogenesis, such as pilonidal sinuses, pilonidal cysts, and dissecting cellulitis (
      • Miller I.M.
      • McAndrew R.J.
      • Hamzavi I.H.
      Prevalence, risk factors, and comorbidities of hidradenitis suppurativa.
      ). Other associations have been described or reported in case reports or smaller studies and are outside the scope of this review article (
      • Kohorst J.J.
      • Kimball A.B.
      • Davis M.D.P.
      Systemic associations of hidradenitis suppurativa.
      ;
      • Miller I.M.
      • McAndrew R.J.
      • Hamzavi I.H.
      Prevalence, risk factors, and comorbidities of hidradenitis suppurativa.
      ).

      Pathogenesis

      Clinical progression of disease

      The mechanism by which aberrant inflammation and changes to the cutaneous microbiome (dysbiosis) lead to disease phenotype is not entirely clear and may involve multiple factors. At a subclinical level, HS is characterized by inappropriate antimicrobial peptide (AMP) and proinflammatory cytokine production by keratinocytes (KCs) (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). These KCs may be intrinsically deficient in certain inflammatory pathways, such as IL-22 production (
      • Jones D.
      • Banerjee A.
      • Berger P.Z.
      • Gross A.
      • McNish S.
      • Amdur R.
      • et al.
      Inherent differences in keratinocyte function in hidradenitis suppurativa: evidence for the role of IL-22 in disease pathogenesis.
      ). IL-22 induces AMP expression, protects against tissue damage, and maintains the mucosal barrier in the intestine (
      • Sabat R.
      • Wolk K.
      Deciphering the role of interleukin-22 in metabolic alterations.
      ;
      • Wang X.
      • Ota N.
      • Manzanillo P.
      • Kates L.
      • Zavala-Solorio J.
      • Eidenschenk C.
      • et al.
      Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes.
      ). Inflammatory damage drives infundibular hyperkeratosis, follicular epithelium hyperplasia, and perifolliculitis (
      • von Laffert M.
      • Stadie V.
      • Wohlrab J.
      • Marsch W.C.
      Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae.
      ). These changes may be exacerbated by impaired Notch signaling and smoking (
      • Hana A.
      • Booken D.
      • Henrich C.
      • Gratchev A.
      • Maas-Szabowski N.
      • Goerdt S.
      • et al.
      Functional significance of non-neuronal acetylcholine in skin epithelia.
      ;
      • Melnik B.C.
      • Plewig G.
      Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa).
      ). An influx of T cells and innate immune cells release chemokines and additional proinflammatory cytokines (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). Eventually, the hair follicles undergo plugging and enlargement, followed by cyst formation (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ).
      Clinical HS becomes appreciable after rupture of the enlarged hair follicle or cyst and spillage of contents, such as bacteria and keratin. These are released from the pilosebaceous unit to the dermis and trigger a neutrophilic foreign body reaction (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). An influx of immune cells and histiocytes ensues, forming multinucleated giant cells that phagocytose the free keratin (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). Proliferation of residual KCs and follicular epithelial strands drives chronic inflammation and formation of sinus tracts and fistulae (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). Bacterial colonies harbored in these tracts may form biofilm that irreversibly binds to hair follicles and sinus tract epithelium, propagating chronic inflammation (
      • Kathju S.
      • Lasko L.A.
      • Stoodley P.
      Considering hidradenitis suppurativa as a bacterial biofilm disease.
      ). Long-standing HS lesions are characterized by B-cell and plasma cell signatures, implicating that later adaptive immune responses may dominate chronic and possibly more severe HS lesions (
      • Gudjonsson J.E.
      • Tsoi L.C.
      • Ma F.
      • Billi A.C.
      • van Straalen K.R.
      • Vossen A.R.J.V.
      • et al.
      Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.
      ).
      Because HS is often a chronic relapsing-remitting disease, large longitudinal studies examining the flux in dysbiosis and immune dysregulation over time may provide insight into the initiating and sustaining events that characterize HS (Figure 2). A rare complication of chronic HS is the development of nonmelanoma skin cancer (NMSC), which typically occurs 20–30 years after the diagnosis of HS (
      • Lapins J.
      • Ye W.
      • Nyrén O.
      • Emtestam L.
      Incidence of cancer among patients with hidradenitis suppurativa.
      ;
      • Losanoff J.E.
      • Sochaki P.
      • Khoury N.
      • Levi E.
      • Salwen W.A.
      • Basson M.D.
      Squamous cell carcinoma complicating chronic suppurative hidradenitis.
      ). Patients with HS have a 4.6-fold greater risk of developing NMSC, especially in the perianal, perineal, and gluteal regions (
      • Lapins J.
      • Ye W.
      • Nyrén O.
      • Emtestam L.
      Incidence of cancer among patients with hidradenitis suppurativa.
      ;
      • Losanoff J.E.
      • Sochaki P.
      • Khoury N.
      • Levi E.
      • Salwen W.A.
      • Basson M.D.
      Squamous cell carcinoma complicating chronic suppurative hidradenitis.
      ).
      Figure thumbnail gr2
      Figure 2Missing studies at the intersection of cutaneous dysbiosis and innate immunity in HS pathogenesis. AMP, antimicrobial peptide; DCD, dermicidin; HS, hidradenitis suppurativa; MMP, matrix metalloproteinase; TLR, toll-like receptor.

      Cutaneous microbiome

      The role of dysbiosis in the pathogenesis of HS remains unclear. Many studies of bacterial cultures harvested from HS skin and deep lesions grew normal cutaneous flora. Staphylococcus aureus, coagulase-negative Staphylococci, and Peptostreptococcus spp. are among the most common organisms identified (
      • Brook I.
      • Frazier E.H.
      Aerobic and anaerobic microbiology of axillary hidradenitis suppurativa.
      ;
      • Lapins J.
      • Jarstrand C.
      • Emtestam L.
      Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery.
      ;
      • Matusiak Ł.
      • Bieniek A.
      • Szepietowski J.C.
      Bacteriology of hidradenitis suppurativa - which antibiotics are the treatment of choice?.
      ;
      • Sartorius K.
      • Killasli H.
      • Oprica C.
      • Sullivan A.
      • Lapins J.
      Bacteriology of hidradenitis suppurativa exacerbations and deep tissue cultures obtained during carbon dioxide laser treatment.
      ) (Table 1). Nicotine alters the skin microbiome by inhibiting the growth of various commensals except S. aureus (
      • Pavia C.S.
      • Pierre A.
      • Nowakowski J.
      Antimicrobial activity of nicotine against a spectrum of bacterial and fungal pathogens.
      ). However, traditional methods of bacterial culture may only reflect a small proportion of the cutaneous microbiome—possibly less than 1% (
      • Grice E.A.
      • Kong H.H.
      • Renaud G.
      • Young A.C.
      NISC Comparative Sequencing Program, Bouffard GG, et al. A diversity profile of the human skin microbiota.
      ).
      Table 1Changes in Relative Microbial Abundance Observed in HS Lesional and Nonlesional Skin
      MicrobeChangeSampleStageMethodReference
      FusobacteriumIncreasedL a, g, gc, o versus NS a, g, gcI/II/III16S and 18S rRNA(
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Coignard-Biehler H.
      • Duchatelet S.
      • Delage M.
      • et al.
      The microbiological landscape of anaerobic infections in hidradenitis suppurativa: a prospective metagenomic study.
      ;
      • Naik H.B.
      • Jo J.H.
      • Paul M.
      • Kong H.H.
      Skin microbiota perturbations are distinct and disease severity–dependent in hidradenitis suppurativa.
      )
      IncreasedL a, gIII16S and 18S rRNA(
      • Ring H.C.
      • Sigsgaard V.
      • Thorsen J.
      • Fuursted K.
      • Fabricius S.
      • Saunte D.M.
      • et al.
      The microbiome of tunnels in hidradenitis suppurativa patients.
      )
      PorphyromonasIncreasedL a, g, gc, oI/II/IIICulture and 16S rRNA(
      • Brook I.
      • Frazier E.H.
      Aerobic and anaerobic microbiology of axillary hidradenitis suppurativa.
      ;
      • Guet-Revillet H.
      • Coignard-Biehler H.
      • Jais J.P.
      • Quesne G.
      • Frapy E.
      • Poirée S.
      • et al.
      Bacterial pathogens associated with hidradenitis suppurativa, France.
      )
      IncreasedL a, g, gc, o versus NS a, g, gcI/II/III16S and 18S rRNA(
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Coignard-Biehler H.
      • Duchatelet S.
      • Delage M.
      • et al.
      The microbiological landscape of anaerobic infections in hidradenitis suppurativa: a prospective metagenomic study.
      ;
      • Ring H.C.
      • Thorsen J.
      • Saunte D.M.
      • Lilje B.
      • Bay L.
      • Riis P.T.
      • et al.
      The follicular skin microbiome in patients with hidradenitis suppurativa and healthy controls.
      )
      IncreasedL a, gIII16S and 18S rRNA(
      • Ring H.C.
      • Sigsgaard V.
      • Thorsen J.
      • Fuursted K.
      • Fabricius S.
      • Saunte D.M.
      • et al.
      The microbiome of tunnels in hidradenitis suppurativa patients.
      )
      PrevotellaIncreasedL a, g, gc, oI/II/IIICulture and 16S rRNA(
      • Brook I.
      • Frazier E.H.
      Aerobic and anaerobic microbiology of axillary hidradenitis suppurativa.
      ;
      • Guet-Revillet H.
      • Coignard-Biehler H.
      • Jais J.P.
      • Quesne G.
      • Frapy E.
      • Poirée S.
      • et al.
      Bacterial pathogens associated with hidradenitis suppurativa, France.
      ;
      • Lapins J.
      • Jarstrand C.
      • Emtestam L.
      Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery.
      )
      IncreasedL a, g, gc, o versus NS a, g, gcI/II/III16S and 18S rRNA(
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Coignard-Biehler H.
      • Duchatelet S.
      • Delage M.
      • et al.
      The microbiological landscape of anaerobic infections in hidradenitis suppurativa: a prospective metagenomic study.
      ;
      • Ring H.C.
      • Thorsen J.
      • Saunte D.M.
      • Lilje B.
      • Bay L.
      • Riis P.T.
      • et al.
      The follicular skin microbiome in patients with hidradenitis suppurativa and healthy controls.
      )
      IncreasedL a, gIII16S and 18S rRNA(
      • Ring H.C.
      • Sigsgaard V.
      • Thorsen J.
      • Fuursted K.
      • Fabricius S.
      • Saunte D.M.
      • et al.
      The microbiome of tunnels in hidradenitis suppurativa patients.
      )
      IncreasedNL a, g, gc versus NS a, g, gcI/II/III16S rRNA(
      • Riverain-Gillet É.
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Duchatelet S.
      • Delage M.
      • et al.
      The surface microbiome of clinically unaffected skinfolds in hidradenitis suppurativa: A cross-sectional culture-based and 16S rRNA gene amplicon sequencing study in 60 patients.
      )
      Staphylococcus aureusIncreasedL a, g, gc, oI/II/IIICulture and 16S rRNA(
      • Brook I.
      • Frazier E.H.
      Aerobic and anaerobic microbiology of axillary hidradenitis suppurativa.
      ;
      • Guet-Revillet H.
      • Coignard-Biehler H.
      • Jais J.P.
      • Quesne G.
      • Frapy E.
      • Poirée S.
      • et al.
      Bacterial pathogens associated with hidradenitis suppurativa, France.
      ;
      • Lapins J.
      • Jarstrand C.
      • Emtestam L.
      Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery.
      ;
      • Matusiak Ł.
      • Bieniek A.
      • Szepietowski J.C.
      Bacteriology of hidradenitis suppurativa - which antibiotics are the treatment of choice?.
      )
      CorynebacteriumIncreasedL a, g, gc, o versus NS a, g, gcI/II/III16S and 18S rRNA(
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Coignard-Biehler H.
      • Duchatelet S.
      • Delage M.
      • et al.
      The microbiological landscape of anaerobic infections in hidradenitis suppurativa: a prospective metagenomic study.
      ;
      • Ring H.C.
      • Thorsen J.
      • Saunte D.M.
      • Lilje B.
      • Bay L.
      • Riis P.T.
      • et al.
      The follicular skin microbiome in patients with hidradenitis suppurativa and healthy controls.
      )
      IncreasedL and NL a, g versus NS a, gI/II/III16S rRNA(
      • Schneider A.M.
      • Cook L.C.
      • Zhan X.
      • Banerjee K.
      • Cong Z.
      • Imamura-Kawasawa Y.
      • et al.
      Loss of skin microbial diversity and alteration of bacterial metabolic function in hidradenitis suppurativa.
      )
      DecreasedL a, g, gc, o versus NS a, g, gcIII16S rRNA(
      • Naik H.B.
      • Jo J.H.
      • Paul M.
      • Kong H.H.
      Skin microbiota perturbations are distinct and disease severity–dependent in hidradenitis suppurativa.
      )
      Coagulase-negative

      Staphylococcus
      IncreasedL a, gI/II/IIICulture(
      • Lapins J.
      • Jarstrand C.
      • Emtestam L.
      Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery.
      ;
      • Matusiak Ł.
      • Bieniek A.
      • Szepietowski J.C.
      Bacteriology of hidradenitis suppurativa - which antibiotics are the treatment of choice?.
      ;
      • Sartorius K.
      • Killasli H.
      • Oprica C.
      • Sullivan A.
      • Lapins J.
      Bacteriology of hidradenitis suppurativa exacerbations and deep tissue cultures obtained during carbon dioxide laser treatment.
      )
      Decreased
      This study reports commensal Staphylococcus but does not distinguish lower classifications.
      L a, g, gc, o versus NS a, g, gcIII16S rRNA(
      • Naik H.B.
      • Jo J.H.
      • Paul M.
      • Kong H.H.
      Skin microbiota perturbations are distinct and disease severity–dependent in hidradenitis suppurativa.
      )
      DecreasedNL a, g, gc versus NS a, g, gcI/II/III16S rRNA(
      • Riverain-Gillet É.
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Duchatelet S.
      • Delage M.
      • et al.
      The surface microbiome of clinically unaffected skinfolds in hidradenitis suppurativa: A cross-sectional culture-based and 16S rRNA gene amplicon sequencing study in 60 patients.
      )
      CutibacteriumDecreasedL a, g, gc, o versus NS a, g, gcI/II/III16S and 18S rRNA(
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Coignard-Biehler H.
      • Duchatelet S.
      • Delage M.
      • et al.
      The microbiological landscape of anaerobic infections in hidradenitis suppurativa: a prospective metagenomic study.
      ;
      • Naik H.B.
      • Jo J.H.
      • Paul M.
      • Kong H.H.
      Skin microbiota perturbations are distinct and disease severity–dependent in hidradenitis suppurativa.
      ;
      • Ring H.C.
      • Thorsen J.
      • Saunte D.M.
      • Lilje B.
      • Bay L.
      • Riis P.T.
      • et al.
      The follicular skin microbiome in patients with hidradenitis suppurativa and healthy controls.
      )
      DecreasedL a, gIII16S and 18S rRNA(
      • Ring H.C.
      • Sigsgaard V.
      • Thorsen J.
      • Fuursted K.
      • Fabricius S.
      • Saunte D.M.
      • et al.
      The microbiome of tunnels in hidradenitis suppurativa patients.
      )
      DecreasedL and NL a, g versus NS a, gI/II/III16S rRNA(
      • Schneider A.M.
      • Cook L.C.
      • Zhan X.
      • Banerjee K.
      • Cong Z.
      • Imamura-Kawasawa Y.
      • et al.
      Loss of skin microbial diversity and alteration of bacterial metabolic function in hidradenitis suppurativa.
      )
      Abbreviations: a, axilla; g, groin; gc, gluteal cleft; HS, hidradenitis suppurativa; L, lesional skin; NL, nonlesional skin; NS, normal skin from healthy donor; o, other sites; rRNA, ribosomal RNA.
      Major microbes with changes in relative abundance across multiple studies are included in the table. Stage reported as Hurley stage of patient according to study. 16S and 18S rRNA denote sequencing of the 16S and 18S bacterial rRNA.
      1 This study reports commensal Staphylococcus but does not distinguish lower classifications.
      More recent studies have utilized metagenomic sequencing to better characterize the cutaneous microbiome (Table 1). Although these studies have similarly identified the predominance of Staphylococcus in early HS lesions, gram-negative anaerobes such as Prevotella and Porphyromonas are predominantly found in chronic suppurating lesions and sinus tracts, hallmarks of moderate to severe disease (
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Coignard-Biehler H.
      • Duchatelet S.
      • Delage M.
      • et al.
      The microbiological landscape of anaerobic infections in hidradenitis suppurativa: a prospective metagenomic study.
      ,
      • Guet-Revillet H.
      • Coignard-Biehler H.
      • Jais J.P.
      • Quesne G.
      • Frapy E.
      • Poirée S.
      • et al.
      Bacterial pathogens associated with hidradenitis suppurativa, France.
      ;
      • Ring H.C.
      • Sigsgaard V.
      • Thorsen J.
      • Fuursted K.
      • Fabricius S.
      • Saunte D.M.
      • et al.
      The microbiome of tunnels in hidradenitis suppurativa patients.
      ,
      • Ring H.C.
      • Thorsen J.
      • Saunte D.M.
      • Lilje B.
      • Bay L.
      • Riis P.T.
      • et al.
      The follicular skin microbiome in patients with hidradenitis suppurativa and healthy controls.
      ).
      Despite these advances in understanding bacterial involvement, it remains unknown whether cutaneous dysbiosis plays a primary or secondary role in the development of HS. The predominance of skin commensals in early HS lesions suggests that primary infection is unlikely to be driving pathogenesis (
      • Lapins J.
      • Jarstrand C.
      • Emtestam L.
      Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery.
      ;
      • Sartorius K.
      • Killasli H.
      • Oprica C.
      • Sullivan A.
      • Lapins J.
      Bacteriology of hidradenitis suppurativa exacerbations and deep tissue cultures obtained during carbon dioxide laser treatment.
      ). Fistulas and sinus tracts encourage formation of bacterial biofilm, which is absent in acute HS lesions but found in a majority of chronic lesions (
      • Okoye G.A.
      • Vlassova N.
      • Olowoyeye O.
      • Agostinho A.
      • James G.
      • Stewart P.S.
      • et al.
      Bacterial biofilm in acute lesions of hidradenitis suppurativa.
      ;
      • Ring H.C.
      • Bay L.
      • Nilsson M.
      • Kallenbach K.
      • Miller I.M.
      • Saunte D.M.
      • et al.
      Bacterial biofilm in chronic lesions of hidradenitis suppurativa.
      ). Tobacco smoke augments biofilm formation in pathogens such as S. aureus (
      • Hutcherson J.A.
      • Scott D.A.
      • Bagaitkar J.
      Scratching the surface – tobacco-induced bacterial biofilms.
      ).
      • Schneider A.M.
      • Cook L.C.
      • Zhan X.
      • Banerjee K.
      • Cong Z.
      • Imamura-Kawasawa Y.
      • et al.
      Loss of skin microbial diversity and alteration of bacterial metabolic function in hidradenitis suppurativa.
      analyzed the differentially activated metabolic pathways of microbiota sampled from HS skin. Microbial metabolic differences between HS and normal skin may reflect dysbiosis; for instance, significant reduction of the skin commensal Cutibacterium in HS may account for decreased propionate and retinol metabolism (
      • Schneider A.M.
      • Cook L.C.
      • Zhan X.
      • Banerjee K.
      • Cong Z.
      • Imamura-Kawasawa Y.
      • et al.
      Loss of skin microbial diversity and alteration of bacterial metabolic function in hidradenitis suppurativa.
      ). Propionic acid possesses antimicrobial properties that inhibit growth of opportunistic pathogens (
      • Shu M.
      • Wang Y.
      • Yu J.
      • Kuo S.
      • Coda A.
      • Jiang Y.
      • et al.
      Fermentation of Propionibacterium acnes, a commensal bacterium in the human skin microbiome, as skin probiotics against methicillin-resistant Staphylococcus aureus.
      ). Another metabolomic study found bacterial cell growth and division processes, such as DNA replication and repair, to be strongly associated with HS lesions (
      • Ring H.C.
      • Thorsen J.
      • Jørgensen A.H.
      • Bay L.
      • Bjarnsholt T.
      • Fuursted K.
      • et al.
      Predictive metagenomic analysis reveals a role of cutaneous dysbiosis in the development of hidradenitis suppurativa.
      ). Perhaps the decreased abundance of critical skin commensals such as Cutibacterium permits growth and division of pathogenic bacteria. More research is needed to confirm the directionality of this relationship and pinpoint the mechanisms by which loss of commensal skin organisms occurs, especially in early stages of disease. Further investigation of the HS bacterial metabolome may permit exploration of treatments such as probiotics and microbiome transplants.
      Complicating the role of cutaneous dysbiosis in disease pathogenesis is the question of whether the inflammation observed in HS is simply an appropriate response to an overabundance or displacement of microbiota or, rather, an aberrant immune response to cutaneous flora (
      • Coates M.
      • Mariottoni P.
      • Corcoran D.L.
      • Kirshner H.F.
      • Jaleel T.
      • Brown D.A.
      • et al.
      The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
      ). Researching nonlesional HS skin, which possesses dysregulated cytokine expression, may illuminate ongoing questions about microbial composition (
      • Kelly G.
      • Hughes R.
      • McGarry T.
      • van den Born M.
      • Adamzik K.
      • Fitzgerald R.
      • et al.
      Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa.
      ). A recent study found that clinically unaffected skinfolds of patients with HS demonstrate a similar abundance of anaerobes such as Prevotella and reduction of skin commensals to lesional skin (
      • Riverain-Gillet É.
      • Guet-Revillet H.
      • Jais J.P.
      • Ungeheuer M.N.
      • Duchatelet S.
      • Delage M.
      • et al.
      The surface microbiome of clinically unaffected skinfolds in hidradenitis suppurativa: A cross-sectional culture-based and 16S rRNA gene amplicon sequencing study in 60 patients.
      ). Perilesional skin is also immunologically dysregulated, and more studies are needed to characterize its microbiome (
      • Kelly G.
      • Hughes R.
      • McGarry T.
      • van den Born M.
      • Adamzik K.
      • Fitzgerald R.
      • et al.
      Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa.
      ).
      Architectural disruptions to the normal structure of the epidermis, dermis, and adnexa are a hallmark of HS. The influence of these structural changes on the skin microbiome remains unclear. One study found that the relative abundance of mixed anaerobes positively correlates with Hurley stage, whereas abundance of skin commensals such as resident Staphylococci, Cutibacterium, and Corynebacterium spp. negatively correlates with Hurley stage (
      • Naik H.B.
      • Jo J.H.
      • Paul M.
      • Kong H.H.
      Skin microbiota perturbations are distinct and disease severity–dependent in hidradenitis suppurativa.
      ). This may indicate that an altered skin architecture relates to microbial changes, because sinus tracts are found in severe HS and characterized by subcutaneous cavities filled with gelatinous material (
      • Ring H.C.
      • Sigsgaard V.
      • Thorsen J.
      • Fuursted K.
      • Fabricius S.
      • Saunte D.M.
      • et al.
      The microbiome of tunnels in hidradenitis suppurativa patients.
      ). Observational studies in patients with HS across different Hurley stages is complicated by confounding factors, such as disease chronicity and treatment regimens, that may directly influence the microbiome. Future studies should examine the skin microbiota in structurally distinct HS lesions, such as abscesses and sinus tracts, within the same patients.
      Another limitation to understanding the cutaneous microbiota in HS is the relative contribution of risk factors and associated conditions to microbial changes. Indeed, smoking, obesity, and diabetes are all associated with unique variations in cutaneous flora (
      • Brandwein M.
      • Katz I.
      • Katz A.
      • Kohen R.
      Beyond the gut: skin microbiome compositional changes are associated with BMI.
      ;
      • Redel H.
      • Gao Z.
      • Li H.
      • Alekseyenko A.V.
      • Zhou Y.
      • Perez-Perez G.I.
      • et al.
      Quantitation and composition of cutaneous microbiota in diabetic and nondiabetic men.
      ;
      • Thompson K.G.
      • Shuster M.
      • Ly B.C.
      • Antonescu C.
      • Florea L.
      • Chien A.L.
      • et al.
      Variability in skin microbiota between smokers, former smokers, and nonsmokers.
      ). S. aureus is found in higher abundance on the foot skin of patients with diabetes, and Corynebacterium spp. are correlated with smoking status and higher BMI, microbial changes that may overlap with those observed in patients with HS (
      • Brandwein M.
      • Katz I.
      • Katz A.
      • Kohen R.
      Beyond the gut: skin microbiome compositional changes are associated with BMI.
      ;
      • Redel H.
      • Gao Z.
      • Li H.
      • Alekseyenko A.V.
      • Zhou Y.
      • Perez-Perez G.I.
      • et al.
      Quantitation and composition of cutaneous microbiota in diabetic and nondiabetic men.
      ;
      • Thompson K.G.
      • Shuster M.
      • Ly B.C.
      • Antonescu C.
      • Florea L.
      • Chien A.L.
      • et al.
      Variability in skin microbiota between smokers, former smokers, and nonsmokers.
      ). Diabetic foot ulcers in particular demonstrate increased abundance of gram-negative anaerobes and formation of biofilm (
      • Jneid J.
      • Lavigne J.P.
      • La Scola B.
      • Cassir N.
      The diabetic foot microbiota: a review.
      ). However, comparisons between cutaneous microbiota of other conditions and HS are limited by heterogeneity of sampling sites and analysis methods.
      To date, there are no longitudinal metagenomic studies that examine the cutaneous microbiota of HS lesions within the same patients over time. Given the relapsing and remitting nature of HS, sampling during disease flares and periods of quiescence may elucidate fluctuations of microbiota and identify dysbiosis predictive of HS disease flares. Additionally, there are currently no studies that have performed metagenomic shotgun sequencing of HS lesional skin. This approach would allow for an unbiased examination of the complete HS microbial landscape, including organisms such as viruses and fungi.
      Capturing the dynamics of microbial changes in HS may inform research on how therapeutics target underlying microbial pathology. In particular, patients receiving antimicrobial and/or immunologic therapy may undergo pronounced alterations of the cutaneous and gastrointestinal microbiome, and the latter itself is associated with inflammatory skin disease (
      • Eppinga H.
      • Sperna Weiland C.J.
      • Thio H.B.
      • van der Woude C.J.
      • Nijsten T.E.C.
      • Peppelenbosch M.P.
      • et al.
      Similar depletion of protective Faecalibacterium prausnitzii in psoriasis and inflammatory bowel disease, but not in hidradenitis suppurativa.
      ;
      • Szántó M.
      • Dózsa A.
      • Antal D.
      • Szabó K.
      • Kemény L.
      • Bai P.
      Targeting the gut-skin axis—probiotics as new tools for skin disorder management?.
      ). Recent studies have begun to explore a potential skin-gut axis in HS; more research comparing the altered cutaneous and gut microbiota in patients with HS is needed (
      • Hispán P.
      • Murcia O.
      • Gonzalez-Villanueva I.
      • Francés R.
      • Giménez P.
      • Riquelme J.
      • et al.
      Identification of bacterial DNA in the peripheral blood of patients with active hidradenitis suppurativa.
      ;
      • Lam S.Y.
      • Radjabzadeh D.
      • Eppinga H.
      • van der Zee H.H.
      • Kraaij R.
      • Konstantinov S.R.
      • et al.
      IDDF2019-ABS-0293 A microbiome pilot study: the exploration of the gut-skin axis in hidradenitis suppurativa.
      ).

      Innate immune pathways

      HS is characterized by aberrant activation of the innate immune system, resulting in release of various molecules and upregulation of pathways that function to protect against pathogenic invasion. In the normal innate immune response, AMPs are secreted by KCs and immune cells to kill invasive pathogens and limit inflammation (
      • Coates M.
      • Blanchard S.
      • MacLeod A.S.
      Innate antimicrobial immunity in the skin: a protective barrier against bacteria, viruses, and fungi.
      ). Studies have identified increased transcript levels of the AMPs β-defensin (BD) 1 to 3 and S100A7 to A9 in HS skin lesions compared with normal skin (
      • Hofmann S.C.
      • Saborowski V.
      • Lange S.
      • Kern W.V.
      • Bruckner-Tuderman L.
      • Rieg S.
      Expression of innate defense antimicrobial peptides in hidradenitis suppurativa.
      ;
      • Schlapbach C.
      • Yawalkar N.
      • Hunger R.E.
      Human beta-defensin-2 and psoriasin are overexpressed in lesions of acne inversa.
      ;
      • Wolk K.
      • Warszawska K.
      • Hoeflich C.
      • Witte E.
      • Schneider-Burrus S.
      • Witte K.
      • et al.
      Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa.
      ). Others have found downregulation of the AMPs BD2 and BD4 in HS lesions relative to normal skin (
      • Dréno B.
      • Khammari A.
      • Brocard A.
      • Moyse D.
      • Blouin E.
      • Guillet G.
      • et al.
      Hidradenitis suppurativa: the role of deficient cutaneous innate immunity.
      ;
      • Mozeika E.
      • Pilmane M.
      • Nürnberg B.M.
      • Jemec G.B.E.
      Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa.
      ). Although
      • Hofmann S.C.
      • Saborowski V.
      • Lange S.
      • Kern W.V.
      • Bruckner-Tuderman L.
      • Rieg S.
      Expression of innate defense antimicrobial peptides in hidradenitis suppurativa.
      demonstrated upregulated BD3 in early HS lesions, they did not identify this increase in Hurley stage III lesions. This relative deficiency of AMP expression may predispose to bacterial infections in severe HS, although there are limited studies on the change in AMP levels with disease progression (
      • Hofmann S.C.
      • Saborowski V.
      • Lange S.
      • Kern W.V.
      • Bruckner-Tuderman L.
      • Rieg S.
      Expression of innate defense antimicrobial peptides in hidradenitis suppurativa.
      ). Furthermore, the expression profiles of individual AMPs should be clarified.
      Recent transcriptome analyses from our group reported genes associated with sweat gland function, including secretoglobins, aquaporin 5, and dermcidin (DCD), to be highly downregulated in HS lesions, whereas S100A8, S100A7, S100A7A, BD2, and other inflammatory factors were upregulated (
      • Coates M.
      • Mariottoni P.
      • Corcoran D.L.
      • Kirshner H.F.
      • Jaleel T.
      • Brown D.A.
      • et al.
      The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
      ). DCD, one of the most downregulated genes identified, is an AMP produced by eccrine sweat glands. Its reduction may signify both diminished secretion and an overall decrease in eccrine sweat glands, indicating a perturbation in skin architecture (
      • Coates M.
      • Mariottoni P.
      • Corcoran D.L.
      • Kirshner H.F.
      • Jaleel T.
      • Brown D.A.
      • et al.
      The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
      ). It is currently unknown whether the dysregulation of AMP levels, in particular the decrease in DCD, is causative of or reactive to cutaneous dysbiosis. Future studies should clarify the directionality of this relationship and identify pathways through which this is mediated.
      Transcriptome analyses of inflammatory pathways in HS skin found upregulation of several genes that encode for molecules in the IFN signaling pathway (
      • Coates M.
      • Mariottoni P.
      • Corcoran D.L.
      • Kirshner H.F.
      • Jaleel T.
      • Brown D.A.
      • et al.
      The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
      ;
      • Gudjonsson J.E.
      • Tsoi L.C.
      • Ma F.
      • Billi A.C.
      • van Straalen K.R.
      • Vossen A.R.J.V.
      • et al.
      Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.
      ;
      • Shanmugam V.K.
      • Jones D.
      • McNish S.
      • Bendall M.L.
      • Crandall K.A.
      Transcriptome patterns in hidradenitis suppurativa: support for the role of antimicrobial peptides and interferon pathways in disease pathogenesis.
      ).
      • Byrd A.S.
      • Carmona-Rivera C.
      • O’Neil L.J.
      • Carlucci P.M.
      • Cisar C.
      • Rosenberg A.Z.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      demonstrated that these upregulated genes are involved in the type I IFN (α/β) pathway. The authors found the presence of neutrophil extracellular traps (NETs) and plasmacytoid dendritic cells (pDCs) localized to these same skin lesions, postulating that NETs activate pDCs to secrete IFN-α (
      • Byrd A.S.
      • Carmona-Rivera C.
      • O’Neil L.J.
      • Carlucci P.M.
      • Cisar C.
      • Rosenberg A.Z.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      ). Another recent study corroborated the upregulation of type I IFN responses using single-cell RNA sequencing of lesional skin (
      • Gudjonsson J.E.
      • Tsoi L.C.
      • Ma F.
      • Billi A.C.
      • van Straalen K.R.
      • Vossen A.R.J.V.
      • et al.
      Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.
      ). Relating back to genetics, a recent study found that type I IFN activation and NF-κB signaling are increased in NCSTN knockdown cell lines (
      • Cao L.
      • Morales-Heil D.J.
      • Roberson E.D.O.
      Nicastrin haploinsufficiency alters expression of type I interferon-stimulated genes: the relationship to familial hidradenitis suppurativa.
      ). This may indicate enhanced inflammatory responsiveness in individuals haploinsufficient for NCSTN, such as patients with familial HS with GSC mutations (
      • Cao L.
      • Morales-Heil D.J.
      • Roberson E.D.O.
      Nicastrin haploinsufficiency alters expression of type I interferon-stimulated genes: the relationship to familial hidradenitis suppurativa.
      ). Future studies should examine if and how GSC mutations regulate type I IFN pathways.
      Although limited, data suggest that matrix metalloproteinases (MMPs) contribute to HS pathogenesis. MMPs are produced by activated fibroblasts to degrade the extracellular matrix and induce tissue destruction (
      • Sanchez J.
      • Le Jan S.
      • Muller C.
      • François C.
      • Renard Y.
      • Durlach A.
      • et al.
      Matrix remodelling and MMP expression/activation are associated with hidradenitis suppurativa skin inflammation.
      ). MMP-2, MMP-8, and MMP-9 are elevated in the lesional skin of patients with HS (
      • Mozeika E.
      • Pilmane M.
      • Nürnberg B.M.
      • Jemec G.B.E.
      Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa.
      ;
      • Sanchez J.
      • Le Jan S.
      • Muller C.
      • François C.
      • Renard Y.
      • Durlach A.
      • et al.
      Matrix remodelling and MMP expression/activation are associated with hidradenitis suppurativa skin inflammation.
      ;
      • Tsaousi A.
      • Witte E.
      • Witte K.
      • Röwert-Huber H.J.
      • Volk H.D.
      • Sterry W.
      • et al.
      MMP8 is increased in lesions and blood of acne inversa patients: a potential link to skin destruction and metabolic alterations.
      ). MMP-8 may offer another mechanistic link to metabolic pathways, as its serum levels negatively correlate with high-density lipoprotein cholesterol, an antiatherogenic lipid, and positively correlate with resistin, a proatherogenic hormone (
      • Tsaousi A.
      • Witte E.
      • Witte K.
      • Röwert-Huber H.J.
      • Volk H.D.
      • Sterry W.
      • et al.
      MMP8 is increased in lesions and blood of acne inversa patients: a potential link to skin destruction and metabolic alterations.
      ). A recent ex vivo HS model demonstrated that high levels of MMP-2 and MMP-9 are associated with pathogenic matrix remodeling and elevation of IL-1β but not IL-17, NLRP3, or caspase-1 (
      • Sanchez J.
      • Le Jan S.
      • Muller C.
      • François C.
      • Renard Y.
      • Durlach A.
      • et al.
      Matrix remodelling and MMP expression/activation are associated with hidradenitis suppurativa skin inflammation.
      ).
      Aberrant complement activation also underlies the innate immune response in HS pathogenesis. Patients with HS have higher serum levels of C5a and C5b-9, and these levels correlate with disease severity (
      • Kanni T.
      • Zenker O.
      • Habel M.
      • Riedemann N.
      • Giamarellos-Bourboulis E.J.
      Complement activation in hidradenitis suppurativa: a new pathway of pathogenesis?.
      ). C5a stimulates the production of TNF-α by PBMCs in vitro (
      • Kanni T.
      • Zenker O.
      • Habel M.
      • Riedemann N.
      • Giamarellos-Bourboulis E.J.
      Complement activation in hidradenitis suppurativa: a new pathway of pathogenesis?.
      ). A transcriptome and proteome analysis of HS skin and blood also found elevated C5a but reduced C3, C4, and iC3b (
      • Hoffman L.K.
      • Tomalin L.E.
      • Schultz G.
      • Howell M.D.
      • Anandasabapathy N.
      • Alavi A.
      • et al.
      Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature.
      ). Given the neutrophilic infiltrate in HS lesions and peripheral blood, it is possible that progressive dysbiosis drives complement dysregulation or vice versa (
      • Byrd A.S.
      • Carmona-Rivera C.
      • O’Neil L.J.
      • Carlucci P.M.
      • Cisar C.
      • Rosenberg A.Z.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      ;
      • Hoffman L.K.
      • Tomalin L.E.
      • Schultz G.
      • Howell M.D.
      • Anandasabapathy N.
      • Alavi A.
      • et al.
      Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature.
      ). The role of complement in modulating the skin microbiome in previous studies raises the question of how cutaneous dysbiosis and aberrant complement activation are related in HS (
      • Chehoud C.
      • Rafail S.
      • Tyldsley A.S.
      • Seykora J.T.
      • Lambris J.D.
      • Grice E.A.
      Complement modulates the cutaneous microbiome and inflammatory milieu.
      ).
      Expression of toll-like receptors (TLRs), a class of pattern recognition receptors, has been investigated with mixed results and may not fully recapitulate TLR activation or function.
      • Hunger R.E.
      • Surovy A.M.
      • Hassan A.S.
      • Braathen L.R.
      • Yawalkar N.
      Toll-like receptor 2 is highly expressed in lesions of acne inversa and colocalizes with C-type lectin receptor.
      identified elevated mRNA and protein levels of TLR2 in HS skin lesions. A later study found downregulation of TLR2–4, TLR7, and TLR9 in lesional skin and nonlesional skin, suggesting a deficient innate immune response (
      • Dréno B.
      • Khammari A.
      • Brocard A.
      • Moyse D.
      • Blouin E.
      • Guillet G.
      • et al.
      Hidradenitis suppurativa: the role of deficient cutaneous innate immunity.
      ). TLR signaling is modulated by Notch, which regulates proinflammatory patterns of gene expression through NF-κB (
      • Palaga T.
      • Buranaruk C.
      • Rengpipat S.
      • Fauq A.H.
      • Golde T.E.
      • Kaufmann S.H.E.
      • et al.
      Notch signaling is activated by TLR stimulation and regulates macrophage functions.
      ). Cigarette smoke and GSC mutations may potentiate defective Notch signaling, promoting disease development through proinflammatory responses (
      • Melnik B.C.
      • Plewig G.
      Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa).
      ,
      • Melnik B.C.
      • Plewig G.
      Impaired Notch-MKP-1 signalling in hidradenitis suppurativa: an approach to pathogenesis by evidence from translational biology.
      ). Impaired Notch signaling results in keratin-enriched epidermal cyst formation and impaired apocrine gland homeostasis (
      • Melnik B.C.
      • Plewig G.
      Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa).
      ,
      • Melnik B.C.
      • Plewig G.
      Impaired Notch-MKP-1 signalling in hidradenitis suppurativa: an approach to pathogenesis by evidence from translational biology.
      ). It may also reduce IL-22 secretion from T cells, although IL-22 production is controlled by additional signaling pathways (
      • Alam M.S.
      • Maekawa Y.
      • Kitamura A.
      • Tanigaki K.
      • Yoshimoto T.
      • Kishihara K.
      • et al.
      Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor.
      ).

      Cytokine signaling

      Although the exact inciting event remains unclear, a proinflammatory milieu underlies perivascular and perifollicular immune cell migration in HS (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). TNF-α, a proinflammatory cytokine produced by dendritic cells (DCs) and macrophages, drives chemotaxis of neutrophils, monocytes, and T cells into the skin (
      • Mozeika E.
      • Pilmane M.
      • Nürnberg B.M.
      • Jemec G.B.E.
      Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa.
      ;
      • van der Zee H.H.
      • de Ruiter L.
      • van den Broecke D.G.
      • Dik W.A.
      • Laman J.D.
      • Prens E.P.
      Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-α and IL-1β.
      ). Multiple studies demonstrated elevated transcript and protein expression of TNF-α in HS lesions and serum (
      • Kelly G.
      • Hughes R.
      • McGarry T.
      • van den Born M.
      • Adamzik K.
      • Fitzgerald R.
      • et al.
      Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa.
      ;
      • Mozeika E.
      • Pilmane M.
      • Nürnberg B.M.
      • Jemec G.B.E.
      Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa.
      ;
      • van der Zee H.H.
      • de Ruiter L.
      • van den Broecke D.G.
      • Dik W.A.
      • Laman J.D.
      • Prens E.P.
      Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-α and IL-1β.
      ). However, decreased levels of TNF-α in HS lesional and nonlesional skin and reduced TNF-α secretion from monocytes compared with healthy controls were seen in other studies (
      • Dréno B.
      • Khammari A.
      • Brocard A.
      • Moyse D.
      • Blouin E.
      • Guillet G.
      • et al.
      Hidradenitis suppurativa: the role of deficient cutaneous innate immunity.
      ;
      • Giamarellos-Bourboulis E.J.
      • Antonopoulou A.
      • Petropoulou C.
      • Mouktaroudi M.
      • Spyridaki E.
      • Baziaka F.
      • et al.
      Altered innate and adaptive immune responses in patients with hidradenitis suppurativa.
      ). Trials of anti–TNF-α therapy support the role of elevated rather than diminished TNF-α in HS pathogenesis (
      • Ghias M.H.
      • Johnston A.D.
      • Kutner A.J.
      • Micheletti R.G.
      • Hosgood H.D.
      • Cohen S.R.
      High-dose, high-frequency infliximab: a novel treatment paradigm for hidradenitis suppurativa.
      ;
      • Kimball A.B.
      • Okun M.M.
      • Williams D.A.
      • Gottlieb A.B.
      • Papp K.A.
      • Zouboulis C.C.
      • et al.
      Two phase 3 trials of adalimumab for hidradenitis suppurativa.
      ;
      • Oskardmay A.N.
      • Miles J.A.
      • Sayed C.J.
      Determining the optimal dose of infliximab for treatment of hidradenitis suppurativa.
      ). TNF-α signaling results in activation of mTOR, a central component of mTOR complex 1 and mTOR complex 2. Anti–TNF-α therapy reduces mTOR expression and quantities of downstream effectors of the mTOR complex 1 pathway in HS lesions (
      • Balato A.
      • Caiazzo G.
      • Annunziata M.C.
      • Marasca C.
      • Scala E.
      • Cacciapuoti S.
      • et al.
      Anti-TNF-α therapy modulates mTORC1 signalling in hidradenitis suppurativa.
      ). A small retrospective study found mTOR inhibition effective in combination with TNF-α blockade for severe HS, and future studies should continue exploring mTOR blockade (
      • Bettuzzi T.
      • Frumholtz L.
      • Jachiet M.
      • Lepelletier C.
      • Djermane M.
      • Cordoliani F.
      • et al.
      Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa.
      ).
      Across various studies, increases in proinflammatory cytokines IL-1β, IL-17, and IL-23 are consistently observed in HS. Mature IL-1β is produced by the inflammasome, a multiprotein complex assembled through the innate immune response. IL-1β promotes the development of CD4+ T helper type (Th) 17 cells, which secrete IL-17 (
      • Sutton C.
      • Brereton C.
      • Keogh B.
      • Mills K.H.G.
      • Lavelle E.C.
      A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis.
      ). Stimulation of Th17 cells is enhanced by IL-23, which is produced by macrophages and DCs (
      • Sabat R.
      • Wolk K.
      • Loyal L.
      • Döcke W.D.
      • Ghoreschi K.
      T cell pathology in skin inflammation.
      ). IL-1β, IL-17, and IL-23 are all elevated at transcript and protein levels in lesional and perilesional HS skin and Th17 cells, the predominant source of IL-17 (
      • Kelly G.
      • Hughes R.
      • McGarry T.
      • van den Born M.
      • Adamzik K.
      • Fitzgerald R.
      • et al.
      Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa.
      ;
      • Schlapbach C.
      • Hänni T.
      • Yawalkar N.
      • Hunger R.E.
      Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa.
      ;
      • van der Zee H.H.
      • Laman J.D.
      • de Ruiter L.
      • Dik W.A.
      • Prens E.P.
      Adalimumab (antitumour necrosis factor-α) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study.
      ,
      • van der Zee H.H.
      • de Ruiter L.
      • van den Broecke D.G.
      • Dik W.A.
      • Laman J.D.
      • Prens E.P.
      Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-α and IL-1β.
      ;
      • Wolk K.
      • Warszawska K.
      • Hoeflich C.
      • Witte E.
      • Schneider-Burrus S.
      • Witte K.
      • et al.
      Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa.
      ). Within the HS lesion, IL-17 stimulates production of chemokines, cytokines, MMPs, and AMPs (
      • Vijatov-Djuric G.
      • Doronjski A.
      • Mitic I.
      • Brkic S.
      • Barisic N.
      Interleukin-17A levels increase in serum of children with juvenile idiopathic arthritis.
      ;
      • Wolk K.
      • Witte E.
      • Warszawska K.
      • Schulze-Tanzil G.
      • Witte K.
      • Philipp S.
      • et al.
      The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis.
      ). IL-1β and IL-17 may employ a positive feedback loop, as IL-17 stimulates release of IL-1β from KCs via activation of the inflammasome protein NLRP3 and caspase-1 (
      • Cho K.A.
      • Suh J.W.
      • Lee K.H.
      • Kang J.L.
      • Woo S.Y.
      IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1β by keratinocytes via the ROS-NLRP3-caspase-1 pathway.
      ;
      • Lima A.L.
      • Karl I.
      • Giner T.
      • Poppe H.
      • Schmidt M.
      • Presser D.
      • et al.
      Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa.
      ).
      Subsequent to chemotaxis to the inflammatory environment, CD4+ T cells undergo differentiation to Th1 cells (
      • Sabat R.
      • Wolk K.
      • Loyal L.
      • Döcke W.D.
      • Ghoreschi K.
      T cell pathology in skin inflammation.
      ). IL-12 is a proinflammatory cytokine elevated in HS skin lesions that is produced by macrophages and DCs and drives this differentiation (
      • Moran B.
      • Sweeney C.M.
      • Hughes R.
      • Malara A.
      • Kirthi S.
      • Tobin A.M.
      • et al.
      Hidradenitis suppurativa is characterized by dysregulation of the Th17:Treg cell axis, which is corrected by anti-TNF therapy.
      ;
      • Sabat R.
      • Wolk K.
      • Loyal L.
      • Döcke W.D.
      • Ghoreschi K.
      T cell pathology in skin inflammation.
      ;
      • Wolk K.
      • Warszawska K.
      • Hoeflich C.
      • Witte E.
      • Schneider-Burrus S.
      • Witte K.
      • et al.
      Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa.
      ). Th1 cells produce IFN-γ, which activates macrophages and traffics immune cells via upregulation of proinflammatory chemokines and adhesion molecules (
      • Schroder K.
      • Hertzog P.J.
      • Ravasi T.
      • Hume D.A.
      Interferon-gamma: an overview of signals, mechanisms and functions.
      ). IFN-γ also establishes a positive feedback loop via induction of CXCR3 ligands, attracting Th1 cells to lesional skin (
      • Van Raemdonck K.
      • Van den Steen P.E.
      • Liekens S.
      • Van Damme J.
      • Struyf S.
      CXCR3 ligands in disease and therapy.
      ). Not all studies have confirmed elevation of IFN-γ in HS lesions, and more evidence is needed to clarify the role of the type II IFN pathway in disease mechanism (
      • Banerjee A.
      • McNish S.
      • Shanmugam V.K.
      Interferon-gamma (IFN-γ) is elevated in wound exudate from hidradenitis suppurativa.
      ;
      • Gudjonsson J.E.
      • Tsoi L.C.
      • Ma F.
      • Billi A.C.
      • van Straalen K.R.
      • Vossen A.R.J.V.
      • et al.
      Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.
      ;
      • Moran B.
      • Sweeney C.M.
      • Hughes R.
      • Malara A.
      • Kirthi S.
      • Tobin A.M.
      • et al.
      Hidradenitis suppurativa is characterized by dysregulation of the Th17:Treg cell axis, which is corrected by anti-TNF therapy.
      ).
      The pathogenesis of HS also involves the anti-inflammatory cytokine IL-10, which has been found at increased levels in HS lesions (
      • van der Zee H.H.
      • Laman J.D.
      • de Ruiter L.
      • Dik W.A.
      • Prens E.P.
      Adalimumab (antitumour necrosis factor-α) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study.
      ;
      • Wolk K.
      • Warszawska K.
      • Hoeflich C.
      • Witte E.
      • Schneider-Burrus S.
      • Witte K.
      • et al.
      Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa.
      ). IL-10 is predominantly produced by macrophages and T lymphocytes and acts to limit proinflammatory cytokine production by macrophages and dampen T-cell activation (
      • van der Zee H.H.
      • Laman J.D.
      • de Ruiter L.
      • Dik W.A.
      • Prens E.P.
      Adalimumab (antitumour necrosis factor-α) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study.
      ). It is unclear if its presence is a response to the proinflammatory environment or is exacerbating dysbiosis and inflammation because of its immunosuppressive effects (
      • Kelly G.
      • Prens E.P.
      Inflammatory mechanisms in hidradenitis suppurativa.
      ).
      Additional signaling molecules with an emerging role in HS include, but are not limited to, IL-6, IL-22, IL-26, IL-32, and IL-36 (
      • Hessam S.
      • Sand M.
      • Gambichler T.
      • Skrygan M.
      • Rüddel I.
      • Bechara F.G.
      Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop.
      ;
      • Scala E.
      • Di Caprio R.
      • Cacciapuoti S.
      • Caiazzo G.
      • Fusco A.
      • Tortorella E.
      • et al.
      A new T helper 17 cytokine in hidradenitis suppurativa: antimicrobial and proinflammatory role of interleukin-26.
      ;
      • Thomi R.
      • Kakeda M.
      • Yawalkar N.
      • Schlapbach C.
      • Hunger R.E.
      Increased expression of the interleukin-36 cytokines in lesions of hidradenitis suppurativa.
      ,
      • Thomi R.
      • Yerly D.
      • Yawalkar N.
      • Simon D.
      • Schlapbach C.
      • Hunger R.E.
      Interleukin-32 is highly expressed in lesions of hidradenitis suppurativa.
      ;
      • Xu H.
      • Xiao X.
      • He Y.
      • Zhang X.
      • Li C.
      • Mao Q.
      • et al.
      Increased serum interleukin-6 levels in patients with hidradenitis suppurativa.
      ). In particular, IL-22 is decreased in HS skin lesions (
      • Hotz C.
      • Boniotto M.
      • Guguin A.
      • Surenaud M.
      • Jean-Louis F.
      • Tisserand P.
      • et al.
      Intrinsic defect in keratinocyte function leads to inflammation in hidradenitis suppurativa.
      ;
      • Wolk K.
      • Warszawska K.
      • Hoeflich C.
      • Witte E.
      • Schneider-Burrus S.
      • Witte K.
      • et al.
      Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa.
      ). Its deficiency may be due to reduced infiltration of IL-22–secreting CD4+ T cells, which are elevated in the serum, but not skin, of patients with HS (
      • Hotz C.
      • Boniotto M.
      • Guguin A.
      • Surenaud M.
      • Jean-Louis F.
      • Tisserand P.
      • et al.
      Intrinsic defect in keratinocyte function leads to inflammation in hidradenitis suppurativa.
      ). A recent study found that serum levels of the proinflammatory cytokines IL-36α, -β, and -γ are elevated in patients with HS who smoke compared with those who do not, although the study did not control for disease severity (
      • Hayran Y.
      • Alli N.
      • Yücel C.
      • Akdoğan N.
      • Turhan T.
      Serum IL-36α, IL-36β, and IL-36γ levels in patients with hidradenitis suppurativa: association with disease characteristics, smoking, obesity, and metabolic syndrome.
      ). These pathways with emerging roles require more characterization in the preclinical and clinical setting.

      Treatment

      Lifestyle

      Weight loss is recommended for management of HS. A systematic review found that weight loss intervention was associated with decreased HS severity in nine observational studies (
      • Sivanand A.
      • Gulliver W.P.
      • Josan C.K.
      • Alhusayen R.
      • Fleming P.J.
      Weight loss and dietary interventions for hidradenitis suppurativa: a systematic review.
      ). A recent crossover study found that weight loss is not associated with a change in IHS4, although this study was limited by small sample size and lack of controls (
      • Damiani G.
      • Mahroum N.
      • Pigatto P.D.M.
      • Pacifico A.
      • Malagoli P.
      • Tiodorovic D.
      • et al.
      The safety and impact of a model of intermittent, time-restricted circadian fasting (“Ramadan Fasting”) on hidradenitis suppurativa: insights from a multicenter, observational, cross-over, pilot, exploratory study.
      ). Prospective randomized controlled trials (RCTs) are needed to elucidate the effects of weight loss on HS disease course.
      Current guidelines suggest evaluation of smoking status and promotion of smoking cessation in patients with HS (
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • Alhusayen R.
      • Brassard A.
      • Burkhart C.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management.
      ;
      • Ingram J.R.
      • Collier F.
      • Brown D.
      • Burton T.
      • Burton J.
      • Chin M.F.
      • et al.
      British Association of Dermatologists guidelines for the management of hidradenitis suppurativa (acne inversa) 2018.
      ). Despite these recommendations, there are no RCTs for this intervention.
      • Simonart T.
      Hidradenitis suppurativa and smoking.
      described two cases of disease remission in patients who underwent tobacco cessation.

      Antimicrobials

      North American and British guidelines recommend antimicrobials for various stages of disease (
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • Alhusayen R.
      • Brassard A.
      • Burkhart C.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management.
      ;
      • Ingram J.R.
      • Collier F.
      • Brown D.
      • Burton T.
      • Burton J.
      • Chin M.F.
      • et al.
      British Association of Dermatologists guidelines for the management of hidradenitis suppurativa (acne inversa) 2018.
      ). For mild disease, clindamycin may be used as topical therapy for HS as it has demonstrated benefit versus placebo in RCTs (
      • Clemmensen O.J.
      Topical treatment of hidradenitis suppurativa with clindamycin.
      ;
      • Jemec G.B.
      • Wendelboe P.
      Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa.
      ). In combination with rifampicin, oral clindamycin is a well-established treatment utilized in cases of tetracycline failure (
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • Alhusayen R.
      • Brassard A.
      • Burkhart C.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management.
      ;
      • Gener G.
      • Canoui-Poitrine F.
      • Revuz J.E.
      • Faye O.
      • Poli F.
      • Gabison G.
      • et al.
      Combination therapy with clindamycin and rifampicin for hidradenitis suppurativa: a series of 116 consecutive patients.
      ). Rifampicin possesses potent activity against bacterial biofilm, in contrast to clindamycin (
      • Mandell J.B.
      • Orr S.
      • Koch J.
      • Nourie B.
      • Ma D.
      • Bonar D.D.
      • et al.
      Large variations in clinical antibiotic activity against Staphylococcus aureus biofilms of periprosthetic joint infection isolates.
      ;
      • Zimmerli W.
      • Sendi P.
      Role of rifampin against staphylococcal biofilm infections in vitro, in animal models, and in orthopedic-device-related infections.
      ). These therapies can also be immunomodulatory by altering NF-κB, activator protein 1, and inducible nitric oxide synthase (iNOS) expression (
      • Frew J.W.
      • Hawkes J.E.
      • Krueger J.G.
      Topical, systemic and biologic therapies in hidradenitis suppurativa: pathogenic insights by examining therapeutic mechanisms.
      ;
      • Yuhas Y.
      • Berent E.
      • Ovadiah H.
      • Azoulay I.
      • Ashkenazi S.
      Rifampin augments cytokine-induced nitric oxide production in human alveolar epithelial cells.
      ). Systemic tetracyclines are recommended as monotherapy in Hurley stage I and II disease (
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • Alhusayen R.
      • Brassard A.
      • Burkhart C.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management.
      ;
      • Ingram J.R.
      • Collier F.
      • Brown D.
      • Burton T.
      • Burton J.
      • Chin M.F.
      • et al.
      British Association of Dermatologists guidelines for the management of hidradenitis suppurativa (acne inversa) 2018.
      ;
      • Zouboulis C.C.
      • Bechara F.G.
      • Dickinson-Blok J.L.
      • Gulliver W.
      • Horváth B.
      • Hughes R.
      • et al.
      Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization – systematic review and recommendations from the HS ALLIANCE working group.
      ). Doxycycline in particular has demonstrated efficacy at killing S. aureus biofilms (
      • Mandell J.B.
      • Orr S.
      • Koch J.
      • Nourie B.
      • Ma D.
      • Bonar D.D.
      • et al.
      Large variations in clinical antibiotic activity against Staphylococcus aureus biofilms of periprosthetic joint infection isolates.
      ). Immunomodulatory effects of tetracyclines include reduction of IL-1, IL-6, IL-8, and TNF-α; downregulation of neutrophil chemotaxis; and suppression of MMP activity and NF-κB signaling (
      • Schmidt K.E.
      • Kuepper J.M.
      • Schumak B.
      • Alferink J.
      • Hofmann A.
      • Howland S.W.
      • et al.
      Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators.
      ;
      • Sun J.
      • Shigemi H.
      • Tanaka Y.
      • Yamauchi T.
      • Ueda T.
      • Iwasaki H.
      Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways.
      ).
      The combination of systemic moxifloxacin, metronidazole, and rifampicin is effective for HS refractory to other treatments (
      • Join-Lambert O.
      • Coignard H.
      • Jais J.P.
      • Guet-Revillet H.
      • Poirée S.
      • Fraitag S.
      • et al.
      Efficacy of rifampin-moxifloxacin-metronidazole combination therapy in hidradenitis suppurativa.
      ). Moxifloxacin is a fluoroquinolone that reduces IL-1β, IL-8, IL-17A, and TNF-α; stabilizes IXb protein; and inhibits NF-κB signaling (
      • Choi J.H.
      • Song M.J.
      • Kim S.H.
      • Choi S.M.
      • Lee D.G.
      • Yoo J.H.
      • et al.
      Effect of moxifloxacin on production of proinflammatory cytokines from human peripheral blood mononuclear cells.
      ;
      • Weiss T.
      • Shalit I.
      • Blau H.
      • Werber S.
      • Halperin D.
      • Levitov A.
      • et al.
      Anti-inflammatory effects of moxifloxacin on activated human monocytic cells: inhibition of NF-kappaB and mitogen-activated protein kinase activation and of synthesis of proinflammatory cytokines.
      ). Metronidazole results in alterations of the gastrointestinal microbiome and glucose metabolism (
      • Rodrigues R.R.
      • Greer R.L.
      • Dong X.
      • DSouza K.N.
      • Gurung M.
      • Wu J.Y.
      • et al.
      Antibiotic-induced alterations in gut microbiota are associated with changes in glucose metabolism in healthy mice.
      ). As IBD and metabolic syndrome are associated with HS, metronidazole may exert indirect anti-inflammatory effects through these changes.
      Carbapenems and linezolid are effective for Hurley stage III HS as a 6-week course (
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • Alhusayen R.
      • Brassard A.
      • Burkhart C.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management.
      ;
      • Chahine A.A.
      • Nahhas A.F.
      • Braunberger T.L.
      • Rambhatla P.V.
      • Hamzavi I.H.
      Ertapenem rescue therapy in hidradenitis suppurativa.
      ;
      • Scheinfeld N.
      Extensive hidradenitis suppurativa (HS) Hurly stage III disease treated with intravenous (IV) linezolid and meropenem with rapid remission.
      ). Both drugs possess anti-inflammatory effects, including reduction of IL-6, IL-12, and TNF-α and inhibition of phagocytosis (
      • Bode C.
      • Muenster S.
      • Diedrich B.
      • Jahnert S.
      • Weisheit C.
      • Steinhagen F.
      • et al.
      Linezolid, vancomycin and daptomycin modulate cytokine production, toll-like receptors and phagocytosis in a human in vitro model of sepsis.
      ;
      • Chahine A.A.
      • Nahhas A.F.
      • Braunberger T.L.
      • Rambhatla P.V.
      • Hamzavi I.H.
      Ertapenem rescue therapy in hidradenitis suppurativa.
      ). Similar to metronidazole, these antibiotics are also associated with changes in the gut microbiome and may indirectly alter disease activity (
      • Dubourg G.
      • Lagier J.C.
      • Robert C.
      • Armougom F.
      • Hugon P.
      • Metidji S.
      • et al.
      Culturomics and pyrosequencing evidence of the reduction in gut microbiota diversity in patients with broad-spectrum antibiotics.
      ).
      Antimicrobial therapy is limited by the relative uncertainty of how much treatment response derives from antibacterial versus anti-inflammatory activity. As such, culture of HS skin lesions for targeted antibiotic therapy is not recommended unless there are signs of secondary infection (
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • Alhusayen R.
      • Brassard A.
      • Burkhart C.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management.
      ). Given the high rates of antibiotic resistance, especially among tetracyclines and clindamycin, antimicrobials may primarily manage disease by countering inflammation, at least after prolonged use (
      • Bettoli V.
      • Manfredini M.
      • Massoli L.
      • Carillo C.
      • Barozzi A.
      • Amendolagine G.
      • et al.
      Rates of antibiotic resistance/sensitivity in bacterial cultures of hidradenitis suppurativa patients.
      ;
      • Fischer A.H.
      • Haskin A.
      • Okoye G.A.
      Patterns of antimicrobial resistance in lesions of hidradenitis suppurativa.
      ). Antibacterial activity may play a prominent role in limiting progression of early HS, whereas in later stages it may decrease microbial trigger for inflammation and eliminate bacterial biofilm (
      • Bettoli V.
      • Manfredini M.
      • Massoli L.
      • Carillo C.
      • Barozzi A.
      • Amendolagine G.
      • et al.
      Rates of antibiotic resistance/sensitivity in bacterial cultures of hidradenitis suppurativa patients.
      ;
      • Fischer A.H.
      • Haskin A.
      • Okoye G.A.
      Patterns of antimicrobial resistance in lesions of hidradenitis suppurativa.
      ). Further studies should examine the antibacterial resistance that may emerge with dual or triple therapy and the effects of gut microbiome changes on HS disease course. Additionally, more randomized prospective studies are needed to guide antimicrobial recommendations, given that current knowledge is mostly limited to retrospective data.

      Immunomodulatory drugs

      In contrast to antimicrobial drugs, immunologic drugs are directed solely toward immunomodulation. Systemic immunosuppression through small molecule drugs yields mixed results; open-label trials and prospective studies involving methotrexate, cyclosporine, and acitretin demonstrate varying degrees of success or are confounded by use of other concurrent therapies (
      • Anderson M.D.
      • Zauli S.
      • Bettoli V.
      • Boer J.
      • Jemec G.B.E.
      Cyclosporine treatment of severe hidradenitis suppurativa--a case series.
      ;
      • Bianchi L.
      • Hansel K.
      • Stingeni L.
      Recalcitrant severe hidradenitis suppurativa successfully treated with cyclosporine A.
      ;
      • Jemec G.B.E.
      Methotrexate is of limited value in the treatment of hidradenitis suppurativa.
      ;
      • Matusiak L.
      • Bieniek A.
      • Szepietowski J.C.
      Acitretin treatment for hidradenitis suppurativa: a prospective series of 17 patients.
      ;
      • Tan M.G.
      • Shear N.H.
      • Walsh S.
      • Alhusayen R.
      Acitretin.
      ).
      Apremilast is a promising small molecule immunomodulator for management of moderate to severe HS, as a recent RCT with 20 patients found 53% of the treatment arm achieving HiSCR at 16 weeks (
      • Vossen A.R.J.V.
      • van Doorn M.B.A.
      • van der Zee H.H.
      • Prens E.P.
      Apremilast for moderate hidradenitis suppurativa: results of a randomized controlled trial.
      ;
      • Weber P.
      • Seyed Jafari S.M.
      • Yawalkar N.
      • Hunger R.E.
      Apremilast in the treatment of moderate to severe hidradenitis suppurativa: a case series of 9 patients.
      ). This drug is a phosphodiesterase 4 inhibitor that regulates inflammatory mediators, such as TNF-α, IL-10, IL-23, and iNOS (
      • Schafer P.
      Apremilast mechanism of action and application to psoriasis and psoriatic arthritis.
      ).
      The efficacy of biologic drugs in inflammatory skin disorders is well documented and may serve as promising treatment for HS (
      • Baker K.F.
      • Isaacs J.D.
      Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?.
      ). Their targeted binding to one or two molecules helps illuminate the roles of different inflammatory pathways in HS pathogenesis based on differential responses to treatment when used empirically and also highlights the heterogeneity of the disease (Figure 3).
      Figure thumbnail gr3
      Figure 3Targeted therapy for HS according to pathogenesis. Keratinocytes inappropriately release AMPs and proinflammatory cytokines, causing infundibular hyperkeratosis and perifolliculitis (
      • von Laffert M.
      • Stadie V.
      • Wohlrab J.
      • Marsch W.C.
      Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae.
      ). The pilosebaceous unit ruptures, releasing keratin and bacteria, the target of antimicrobial drugs (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). Complement is aberrantly activated, increasing levels of C5b–C9, which form the MAC, and C5a, a neutrophil chemotaxin targeted by the mAb IFX-1 (
      • Kanni T.
      • Zenker O.
      • Habel M.
      • Riedemann N.
      • Giamarellos-Bourboulis E.J.
      Complement activation in hidradenitis suppurativa: a new pathway of pathogenesis?.
      ). Macrophages are recruited and produce IL-6, IL-10, TNF-α, and IL-1 (
      • van der Zee H.H.
      • Laman J.D.
      • Boer J.
      • Prens E.P.
      Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments.
      ). TNF-α is also produced by DCs; it is targeted by the mAbs infliximab and adalimumab and the decoy receptor etanercept (
      • Adams D.R.
      • Yankura J.A.
      • Fogelberg A.C.
      • Anderson B.E.
      Treatment of hidradenitis suppurativa with etanercept injection.
      ;
      • Grant A.
      • Gonzalez T.
      • Montgomery M.O.
      • Cardenas V.
      • Kerdel F.A.
      Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial.
      ;
      • Kimball A.B.
      • Okun M.M.
      • Williams D.A.
      • Gottlieb A.B.
      • Papp K.A.
      • Zouboulis C.C.
      • et al.
      Two phase 3 trials of adalimumab for hidradenitis suppurativa.
      ;
      • Pelekanou A.
      • Kanni T.
      • Savva A.
      • Mouktaroudi M.
      • Raftogiannis M.
      • Kotsaki A.
      • et al.
      Long-term efficacy of etanercept in hidradenitis suppurativa: results from an open-label phase II prospective trial.
      ). Adalimumab is currently the only FDA-approved mAb therapy for HS (
      • Kimball A.B.
      • Okun M.M.
      • Williams D.A.
      • Gottlieb A.B.
      • Papp K.A.
      • Zouboulis C.C.
      • et al.
      Two phase 3 trials of adalimumab for hidradenitis suppurativa.
      ). IL-1 is blocked by the mAbs anakinra (targeting IL-1α) and bermekimab (targeting IL-1R) (
      • Kanni T.
      • Argyropoulou M.
      • Spyridopoulos T.
      • Pistiki A.
      • Stecher M.
      • Dinarello C.A.
      • et al.
      MABp1 targeting IL-1α for moderate to severe hidradenitis suppurativa not eligible for adalimumab: a randomized study.
      ;
      • Tzanetakou V.
      • Kanni T.
      • Giatrakou S.
      • Katoulis A.
      • Papadavid E.
      • Netea M.G.
      • et al.
      Safety and efficacy of anakinra in severe hidradenitis suppurativa: a randomized clinical trial.
      ). Mature IL-1β, synthesized from the inflammasome, stimulates the development of CD4+ Th17 cells. Activation of these cells is also enhanced by IL-23 (
      • Sabat R.
      • Wolk K.
      • Loyal L.
      • Döcke W.D.
      • Ghoreschi K.
      T cell pathology in skin inflammation.
      ). CD4+ Th17 cells produce IL-17, which is targeted by the mAbs secukinumab (IL-17A), bimekizumab (IL-17A/IL-17F), and brodalumab (IL-17RA) (
      • Baker K.F.
      • Isaacs J.D.
      Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?.
      ;
      • Thorlacius L.
      • Theut Riis P.
      • Jemec G.B.E.
      Severe hidradenitis suppurativa responding to treatment with secukinumab: a case report.
      ). Both macrophages and DCs stimulate production of IL-12 and IL-23. IL-12 drives Th1 differentiation to yield IFN-γ production. IL-23 stimulates Th17 cell differentiation and is targeted by the mAbs guselkumab and risankizumab (
      • Baker K.F.
      • Isaacs J.D.
      Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?.
      ;
      • Kearney N.
      • Byrne N.
      • Kirby B.
      • Hughes R.
      Successful use of guselkumab in the treatment of severe hidradenitis suppurativa.
      ;
      • Kovacs M.
      • Podda M.
      Guselkumab in the treatment of severe hidradenitis suppurativa.
      ). Both IL-12 and IL-23 are targeted by the mAb ustekinumab (
      • Blok J.L.
      • Li K.
      • Brodmerkel C.
      • Horvátovich P.
      • Jonkman M.F.
      • Horváth B.
      Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum.
      ;
      • Sharon V.R.
      • Garcia M.S.
      • Bagheri S.
      • Goodarzi H.
      • Yang C.
      • Ono Y.
      • et al.
      Management of recalcitrant hidradenitis suppurativa with ustekinumab.
      ). AMP, antimicrobial peptide; DC, dendritic cell; FDA, Food and Drug Administration; HS, hidradenitis suppurativa; MAC, membrane attack complex; Th, T helper type.
      Currently, the anti–TNF-α mAb adalimumab is the only Food and Drug Administration–approved biologic therapy for HS, proving effective in two large phase III trials (PIONEER I and II) (
      • Kimball A.B.
      • Okun M.M.
      • Williams D.A.
      • Gottlieb A.B.
      • Papp K.A.
      • Zouboulis C.C.
      • et al.
      Two phase 3 trials of adalimumab for hidradenitis suppurativa.
      ). Infliximab, another mAb against TNF-α, has demonstrated efficacy in a phase II RCT, although phase III RCTs have yet to be performed (
      • Grant A.
      • Gonzalez T.
      • Montgomery M.O.
      • Cardenas V.
      • Kerdel F.A.
      Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial.
      ). Retrospective data suggest that doses greater than the manufacturer-recommended 5 mg/kg every 8 weeks may be required; a majority received initial injections at 10 mg/kg and maintenance dose of 10 mg/kg every 6–8 weeks and required dose escalation after one year of therapy (
      • Oskardmay A.N.
      • Miles J.A.
      • Sayed C.J.
      Determining the optimal dose of infliximab for treatment of hidradenitis suppurativa.
      ). Another recent study with initial infliximab doses of 7.5 mg/kg every 4 weeks found that 50% of patients who did not achieve clinical response were able to do so after dose escalation to 10 mg/kg every 4 weeks (
      • Ghias M.H.
      • Johnston A.D.
      • Kutner A.J.
      • Micheletti R.G.
      • Hosgood H.D.
      • Cohen S.R.
      High-dose, high-frequency infliximab: a novel treatment paradigm for hidradenitis suppurativa.
      ). A recent study by
      • Lowe M.M.
      • Naik H.B.
      • Clancy S.
      • Pauli M.
      • Smith K.M.
      • Bi Y.
      • et al.
      Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy.
      found that patients with an enriched B-cell signature within lesional skin had significantly lower response rates to anti–TNF-α therapy. Efficacy of the soluble TNF-α decoy receptor etanercept in HS remains inconclusive; although it was ineffective in a RCT, an open phase II trial found improvement in long-term disease course (
      • Adams D.R.
      • Yankura J.A.
      • Fogelberg A.C.
      • Anderson B.E.
      Treatment of hidradenitis suppurativa with etanercept injection.
      ;
      • Pelekanou A.
      • Kanni T.
      • Savva A.
      • Mouktaroudi M.
      • Raftogiannis M.
      • Kotsaki A.
      • et al.
      Long-term efficacy of etanercept in hidradenitis suppurativa: results from an open-label phase II prospective trial.
      ).
      Other biologic drugs studied or under investigation for HS treatment target cytokines with altered levels in disease. Anakinra and bermekimab, drugs that block IL-1, have demonstrated HiSCR response in 78% and 60% of patients, respectively, at 12 weeks in RCTs (
      • Kanni T.
      • Argyropoulou M.
      • Spyridopoulos T.
      • Pistiki A.
      • Stecher M.
      • Dinarello C.A.
      • et al.
      MABp1 targeting IL-1α for moderate to severe hidradenitis suppurativa not eligible for adalimumab: a randomized study.
      ;
      • Tzanetakou V.
      • Kanni T.
      • Giatrakou S.
      • Katoulis A.
      • Papadavid E.
      • Netea M.G.
      • et al.
      Safety and efficacy of anakinra in severe hidradenitis suppurativa: a randomized clinical trial.
      ). Notably, the bermekimab trial recruited patients who failed or were unable to receive adalimumab (
      • Kanni T.
      • Argyropoulou M.
      • Spyridopoulos T.
      • Pistiki A.
      • Stecher M.
      • Dinarello C.A.
      • et al.
      MABp1 targeting IL-1α for moderate to severe hidradenitis suppurativa not eligible for adalimumab: a randomized study.
      ).
      Ustekinumab is an mAb against IL-12 and IL-23 that achieved HiSCR in 47% of patients at week 40 in an open phase II trial and has shown success in numerous case reports (
      • Blok J.L.
      • Li K.
      • Brodmerkel C.
      • Horvátovich P.
      • Jonkman M.F.
      • Horváth B.
      Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum.
      ;
      • Gulliver W.P.
      • Jemec G.B.E.
      • Baker K.A.
      Experience with ustekinumab for the treatment of moderate to severe hidradenitis suppurativa.
      ;
      • Santos-Pérez M.I.
      • García-Rodicio S.
      • Del Olmo-Revuelto M.A.
      • Pozo-Román T.
      Ustekinumab for hidradenitis suppurativa: a case report.
      ;
      • Sharon V.R.
      • Garcia M.S.
      • Bagheri S.
      • Goodarzi H.
      • Yang C.
      • Ono Y.
      • et al.
      Management of recalcitrant hidradenitis suppurativa with ustekinumab.
      ). A small retrospective study of guselkumab, an mAb against IL-23, found the drug to be effective in 63% of patients with moderate to severe HS (
      • Casseres R.G.
      • Kahn J.S.
      • Her M.J.
      • Rosmarin D.
      Guselkumab in the treatment of hidradenitis suppurativa: a retrospective chart review.
      ), with several case reports or series thereafter confirming successful treatment (
      • Kearney N.
      • Byrne N.
      • Kirby B.
      • Hughes R.
      Successful use of guselkumab in the treatment of severe hidradenitis suppurativa.
      ;
      • Kovacs M.
      • Podda M.
      Guselkumab in the treatment of severe hidradenitis suppurativa.
      ). Currently, a phase II trial is being conducted to evaluate the drug (
      ClinicalTrials.gov
      A study to evaluate the efficacy, safety, and tolerability of guselkumab for the treatment of participants with moderate to severe hidradenitis suppurativa (HS) (NOVA).
      ). A phase II trial is also underway for risankizumab, another mAb that targets IL-23 (
      ClinicalTrials.gov
      A global study comparing risankizumab to placebo in adult participants with moderate to severe hidradenitis suppurativa (DETERMINED 1).
      ). Clinical responses to these therapies are of particular interest as their results may indicate the relative contributions of the IL-12/Th1 and IL-23/Th17 pathways to HS pathogenesis.
      Antibody blockade of IL-17 has also been investigated. There are case reports showing successful treatment of moderate to severe HS with the anti–IL-17A mAb secukinumab, and a recent open pilot trial reported that 67% of patients achieved HiSCR after 24 weeks of therapy (
      • Giuseppe P.
      • Nicola P.
      • Valentina C.
      • Elena C.
      • Salvatrice C.
      • Rosario G.
      • et al.
      A case of moderate hidradenitis suppurativa and psoriasis treated with secukinumab.
      ;
      • Jørgensen A.H.R.
      • Yao Y.
      • Thomsen S.F.
      Therapeutic response to secukinumab in a 36-year-old woman with hidradenitis suppurativa.
      ;
      • Prussick L.
      • Rothstein B.
      • Joshipura D.
      • Saraiya A.
      • Turkowski Y.
      • Abdat R.
      • et al.
      Open-label, investigator-initiated, single-site exploratory trial evaluating secukinumab, an anti-interleukin-17A monoclonal antibody, for patients with moderate-to-severe hidradenitis suppurativa.
      ;