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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, USAPinnell Center for Investigative Dermatology, Duke University School of Medicine, Durham, North Carolina, USADuke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USADepartment of Immunology, Duke University School of Medicine, Durham, North Carolina, USADepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USADuke Microbiome Center, Duke University Medical Center, Durham, North Carolina, USA
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.
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 (
The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
). 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 (
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 (
Various other staging systems exist, including the HS Sartorius score, Physician Global Assessment, and International Hidradenitis Suppurativa Severity Score System (IHS4), among others (
). 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 (
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 (
). 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 (
). 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 (
). 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 (
). 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 (
There exists an association between metabolic syndrome, a cluster of cardiometabolic conditions including obesity, insulin resistance, hypertension, and lipid abnormalities, and HS (
). 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 (
). 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 (
). Studies have identified loss-of-function mutations in the PSENEN, NCSTN, and PSEN1 genes, which encode for components of the γ-secretase complex (GSC) (
). 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 (
). 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 (
). 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 (
). 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 (
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 (
). 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 (
). 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 (
Pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH): a new autoinflammatory syndrome associated with a novel mutation of the PSTPIP1 gene.
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 (
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 (
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) (
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 (
). Bacterial colonies harbored in these tracts may form biofilm that irreversibly binds to hair follicles and sinus tract epithelium, propagating chronic inflammation (
). 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 (
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 (
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 (
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.
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.
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.
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.
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.
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.
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 (
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 (
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.
). Fistulas and sinus tracts encourage formation of bacterial biofilm, which is absent in acute HS lesions but found in a majority of chronic lesions (
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 (
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 (
). 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 (
The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
). 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 (
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.
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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
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 (
). 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 (
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 (
). 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 (
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 (
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 (
The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
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 (
). This may indicate enhanced inflammatory responsiveness in individuals haploinsufficient for NCSTN, such as patients with familial HS with GSC mutations (
). 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 (
). 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 (
). 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 (
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 (
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 (
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 (
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.
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 (
). TNF-α, a proinflammatory cytokine produced by dendritic cells (DCs) and macrophages, drives chemotaxis of neutrophils, monocytes, and T cells into the skin (
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.
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 (
). 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 (
). 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 (
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 (
). 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 (
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.
). 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 (
). Th1 cells produce IFN-γ, which activates macrophages and traffics immune cells via upregulation of proinflammatory chemokines and adhesion molecules (
). 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 (
). IL-10 is predominantly produced by macrophages and T lymphocytes and acts to limit proinflammatory cytokine production by macrophages and dampen T-cell activation (
). It is unclear if its presence is a response to the proinflammatory environment or is exacerbating dysbiosis and inflammation because of its immunosuppressive effects (
Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop.
). 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 (
). 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 (
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 (
). 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 (
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.
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.
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.
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.
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.
Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization – systematic review and recommendations from the HS ALLIANCE working group.
). 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 (
Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways.
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.
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.
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 (
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 (
). 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 (
). 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 (
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 (
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 3Targeted therapy for HS according to pathogenesis. Keratinocytes inappropriately release AMPs and proinflammatory cytokines, causing infundibular hyperkeratosis and perifolliculitis (
). Mature IL-1β, synthesized from the inflammasome, stimulates the development of CD4+ Th17 cells. Activation of these cells is also enhanced by IL-23 (
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?.
). 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 (
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?.
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) (
). 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 (
). 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 (
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 (
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 (
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 (
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).
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 (
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