1055920 research-article20212021 TAJ0010.1177/20406223211055920Therapeutic Advances in Chronic DiseaseV Amat-Samaranch, E Agut-Busquet Therapeutic Advances in Chronic Disease Review New perspectives on the treatment of Ther Adv Chronic Dis 2021, Vol. 12: 1–34 hidradenitis suppurativa DOI: 10.1177/ https://doi.org/10.1177/20406223211055920 https://doi.org/10.1177/20406223211055920 20406223211055920 © The Author(s), 2021. Article reuse guidelines: Victoria Amat-Samaranch, Eugènia Agut-Busquet, Eva Vilarrasa and Lluís Puig sagepub.com/journals- permissions Abstract: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the presence of painful nodules, abscesses, chronically draining fistulas, and scarring in apocrine gland-bearing areas of the body. The exact pathogenesis of HS is not yet well understood, but there is a consensus in considering HS a multifactorial disease with a genetic predisposition, an inflammatory dysregulation, and an influence of environmental modifying factors. Therapeutic approach of HS is challenging due to the wide clinical manifestations of the disease and the complex pathogenesis. This review describes evidence for effectiveness of current and emerging HS therapies. Topical therapy, systemic treatments, biological agents, surgery, and light therapy have been used for HS with variable results. Adalimumab is the only US Food and Drug Administration (FDA) approved biologic agent for moderate-to-severe HS, but new therapeutic options are being studied, targeting different specific cytokines involved in HS pathogenesis. Comparing treatment outcomes between therapies is difficult due to the lack of randomized controlled trials. Treatment strategy should be selected in concordance to disease severity and requires combination of treatments in most cases. Keywords: acne inversa, anti-IL-17, anti-TNF-alpha, biologics, hidradenitis suppurativa, small molecules, therapies Received: 12 May 2021; revised manuscript accepted: 8 October 2021 Introduction in a recent two-step cluster analysis of Correspondence to: Lluís Puig Hidradenitis suppurativa (HS) is a chronic, Mediterranean patients that included biomarkers, Department of relapsing, inflammatory skin disease character- two endotypic clusters have been identified: clus- Dermatology, Hospital de la Santa Creu i Sant Pau, ized by the inflammation of hair follicles in apo- ter 1 (65% of patients) is characterized by non- Universitat Autònoma de crine gland-bearing areas of the body, manifesting obese males with early onset HS, nodular lesions Barcelona, Mas Casanovas 90, 08041 Barcelona, as painful nodules, abscesses, chronically drain- in posterior sites, history of pilonidal sinus, high Spain. ing fistulas, and scarring.1,2 It is a disabling dis- serum levels of IL-10, and presence of gamma- lpuig@santpau.cat ease with great psychological and functional secretase mutations; and cluster 2 (35% of Victoria Amat-Samaranch impact on patients due to pain and malodorous patients), characterized by obese females or males Eugènia Agut-Busquet discharge of the lesions. Prevalence estimates with later onset HS, lesions in anterior sites, more Eva Vilarrasa Department of vary depending on the method of data collection sinuses and abscesses, less nodules, and higher Dermatology, Hospital de and ethnic background, but range between 0.7% serum concentrations of IL-1, C-reactive protein, la Santa Creu i Sant Pau, Universitat Autònoma de and 1.2%, according to the largest cross-sectional IL-17, and IL-6, which is more related to sys- Barcelona, Mas Casanovas and registry-based studies;3 in most patients, temic inflammation.5 90, 08041, Barcelona, Spain onset of HS takes place after puberty, and the disease predominantly affects women in Western The pathogenesis of HS is not yet well under- countries.4 stood, but there is a consensus in considering HS a multifactorial disease with implication of Due to the polymorphic nature of HS manifesta- different immunological factors.6–8 This makes tions and patient characteristics, several attempts HS a complex disease with a challenging at phenotypic classification have been published; approach.9 journals.sagepub.com/home/taj 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Chronic Disease 12 Table 1. Hurley score. Hurley score Hurley I Single or multiple isolated nodules and abscesses without sinus tracts or scarring Hurley II Recurrent abscesses with ⩾1 sinus tracts and scarring, separated by normal skin Hurley III Multiple lesions coalescing into inflammatory plaques, with extensive sinuses and scarring involving the entire region Refined Hurley score  Absence of Hurley I sinus tracts A: ⩽2 involved areas and <5 abscesses or nodules B: >2 body areas or ⩾5 abscesses or nodules – predominantly fixed lesions C: >2 body areas or ⩾5 abscesses or nodules – migratory lesions  Presence of Hurley II sinus tracts A: <1% of BSA, without abscesses or nodules B: <1% of BSA, with ⩽2 affected body areas with abscesses or nodules  C: <1% of BSA, with >2 affected body areas with abscesses or nodules Hurley III: ⩾1% of BSA of the involved body site with interconnected inflammatory sinus tracts BSA, Body Surface Area. While mild disease can be usually controlled with number of affected areas and fails to assess disease lifestyle modifications, weight loss, stop smoking, activity or treatment response. In an attempt to topical treatment, and oral antibiotics, manage- solve these limitations, the Refined Hurley staging ment of moderate-to-severe HS, frequently has been proposed (Table 1).12 Abscess and nodule refractory to conventional treatments,10 is a great counts (AN count) is feasible to perform in clinical challenge for clinicians, and new therapeutic ave- practice and may facilitate therapeutic decisions.9 nues are under study. In research settings, the Hidradenitis Suppurativa The aim of this article is to provide a narrative Clinical Response (HiSCR) is the most validated review of current, new, and future potential treat- and widely used measure for assessing treatment ments of HS, with a special focus on medical response. Patients who achieve HiSCR should modalities. A PubMed search was conducted, show a 50% reduction in the sum of abscesses including the terms ‘hidradenitis suppurativa’, and inflammatory nodules, no increase in the ‘treatment’, OR ‘therapy’, and the different treat- number of abscesses, and no increase in the num- ments discussed in this article. Also, all the clini- ber of draining fistulas from baseline.13 The cal trials of HS in www.clinicaltrials.gov were Modified Sartorius Score (mSS), the Hidradenitis reviewed. To be included, studies had to discuss Suppurativa Physician’s Global Assessment HS and treatment as a primary theme, be written (HS-PGA), the Hidradenitis Suppurativa Severity in English, and be published in a peer-reviewed Index (HSSI), and the International Hidradenitis journal. After collecting the information, we col- Suppurativa Severity Score System (ISH4)14 are lated, summarized, and reported the results using used in clinical trials too (Tables 2 and 3).9 The narrative synthesis. last four are also useful in daily practice. Disease severity and outcome measures Pathogenesis Numerous tools have been described for assess- Genetic, environmental, and immunologic factors ment of patients with HS. Hurley staging has been intervene in the pathogenesis of HS (Figure 1).15 recommended in the clinical setting,9 since it is simple and helps determine therapeutic needs Approximately 30% of patients with HS have a (Table 1).11 However, it does not count the positive family history. Monogenic HS is rare and 2 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. Table 2. Other outcome measures used in clinical trials. HS-PGA Clear: 0 0 abscesses 0 draining fistulas 0 inflammatory nodules 0 non-inflammatory nodules Minimal: 1 0 abscesses 0 draining fistulas 0 inflammatory nodules ⩾1 non-inflammatory nodules Mild: 2 0 abscesses, 0 draining fistulas, 1–4 inflammatory nodules OR 1 abscess or draining fistula and 0 inflammatory nodules Moderate: 3 0 abscesses, 0 draining fistulas, ⩾5 inflammatory nodules OR 1 abscess or draining fistula and ⩾1 inflammatory nodule OR 2–5 abscesses or draining fistulas and <10 inflammatory nodules Severe: 4 2–5 abscesses or draining fistulas ⩾10 inflammatory nodules Very severe: 5 >5 abscesses or draining fistulas HSSI Number Body surface Number of No. of dressing Pain (visual of sites area inflammatory changes during analog lesions work hours scale) Stage 0 0 0 0 0 0–1 Stage 1 1 1 1–2 0 0–1 Stage 2 2 2–3 2–3 1 2–4 Stage 3 3 4–5 4–5 >1 5–7 Stage 4 ⩾4 >5 >5 >1 8–10 mSS Anatomic regions affected 3 points per each region affected: axilla, groin, gluteal, other Number and type of 1 point for nodule lesions 6 points for fistula (per each region) Longest distance between 1 point if <5 cm two lesions 3 points if 5–10 cm 9 points if >10 cm If one lesion, use same point system for size of lesion Lesions clearly separated 0 points if yes by normal skin 9 points if no HS-PGA, Hidradenitis Suppurativa Physician’s Global Assessment; HSSI, Hidradenitis Suppurativa Severity Index; mSS, Modified Sartorius Score. journals.sagepub.com/home/taj 3 Therapeutic Advances in Chronic Disease 12 Table 3. IHS4. IHS4 (points) = number of nodules × 1 + number of abscesses × 2 + number of draining tunnels (fistulas/ sinuses) × 4 Mild HS: ⩽3 points Moderate HS: 4–10 points Severe HS: ⩾11 points HS, hidradenitis suppurativa; IHS4, International Hidradenitis Suppurativa Severity Score System. Figure 1. Causes of HS: Genetic, environmental, and immunologic factors intervene in the pathogenesis of HS. Monogenic HS can be divided into defects in Notch and γ-Secretase signaling pathways (PSENEN, NCSTN and PSEN1, POFUT1, POGLUT1) and defects in inflammasome function (NLRP3, MEFV, NOD2, NLRP12, LPIN2). Lifestyle factors including friction, smoking, obesity, and a dysbiosis have demonstrated to be contributors to HS development. LPIN2, lipin 2; MEFV, Mediterranean fever; NCSTN, nicastrin; NLRP3, nucleotide-binding domain leucine-rich repeat containing protein 3; NOD2 and PSTPIP1, proline-serine-threonine-phosphatase-interactive protein 1; POFUT1, O-fructosyltransferase 1; POGLUT1, protein O-glucosyltransferase 1; PSEN, presenilin; PSENEN, presenilin enhancer, gamma-secretase subunit. can be classified into (1) defects in Notch and γ- and differentiation) that leads to hyperkeratiniza- secretase signaling pathways that lead to a severe tion of the follicular epithelium, abnormal comedone-predominant HS phenotype and (2) keratinocyte differentiation, disruption of the defects in inflammasome function that results in normal hair follicle cycle, and formation of an inflammatory phenotype of HS with additional follicular cysts.21,22 Mutations in POFUT1 systemic features (Figure 1).16 (O-fructosyltransferase 1), and POGLUT1 (protein O-glucosyltransferase 1), which have also been The genes encoding for proteins of the γ-secretase involved in decreased Notch signaling, have been transmembrane complex with most widely described in patients with concomitant HS and described mutations in HS are PSENEN (coding Dowling-Degos disease.23,24 Also mutation in for presenilin enhancer), NCSTN (nicastrin), and nicastrin have been reported in patients with HS PSEN1 (presenilin-1).17 These mutations usually and Dowling-Degos disease.25 show familiar aggregation with autosomal domi- nant inheritance and incomplete penetration but As regards inflammasome dysfunction, it is rec- have also been observed in sporadic cases.17–20 ognized as a central driver for many autoinflam- These mutations result in reduced signaling of matory disorders, some of them associated to HS, the Notch pathway (involved in cell maturation such as Familial Mediterranean fever (MEFV 4 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. Figure 2. Early stage HS: The first event in HS lesions is hyperkeratosis and hyperplasia of the infundibular epithelium (1), produced by chronic friction, genetic predisposition, and environmental factors. This leads to follicular ‘plugging’, follicular dilatation (2), and eventual rupture (3). Bacteria and cellular debris including pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) are released to the dermis initiating an innate immune response when recognized by TLRs. PAMPs and DAMPs activate the inflammasome response involving the NOD-like receptor protein 3 (NLRP3) in macrophages and neutrophils with subsequent activation of caspase-1 and activation of proinflammatory cytokines such as IL-1β. IL-1β provokes the production of chemokines by fibroblasts (CXCL1 and CXCL6) that will mainly attract neutrophils. TNF-α, secreted by macrophages and dendritic cells, induces the production by keratinocytes of a wide range of chemokines (CXCL8, CXCL11, CCL20, and CCL2), which attract neutrophils, subsets of T cells, and monocytes into the skin. Activated dendritic cells, through the production of IL-23 and IL-12, promote polarization of CD4+ T cells toward Th17 and Th1 cells, respectively. Activation of the complement pathway contributes to neutrophil activation and recruitment by C3a and C5a. mutation).26,27 Inflammasome upregulation spondyloarthritis, inflammatory bowel disease (PSTPIP1 mutation) has also been demonstrated (IBD), and psoriasis.37 in pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and pyoderma gan- Skin microbiota is also considered an environ- grenosum, acne, arthritis, and HS (PAPASH) mental causative factor for HS. A pattern of cuta- syndrome.28,29 In the pyoderma gangrenosum, neous dysbiosis has been associated to HS acne, and HS (PASH) syndrome, diverse muta- pathogenesis after observing bacterial coloniza- tions in the Notch signaling pathway and inflam- tion of superficial and deep HS lesions.38 Bacteria masome function genes (NCSTN, NOD2, play a major role in the activation of the innate MEFV, NLRP3, NLRP12, PSTPIP1, LPIN2) immunologic response (see below), and it is also have been reported.16,30 thought to play a role in the maintenance of the inflammatory response.39 The exact mechanism Environmental factors such as mechanical of the influence of microbiome in HS immuno- stress,31 obesity,32 diabetes,32 metabolic syn- logic response is not fully understood.38 drome,33 diet,34 smoking,35 and hormonal fac- tors36 are known to contribute to the development Follicular occlusion is the first event observed in or exacerbation of HS (Figure 1). Furthermore, early lesions; it is produced by infundibular ker- HS has been associated to comorbidities sharing atosis and hyperplasia of the follicular epithe- immunological dysregulation, such as axial lium (Figure 2). Local cell damage caused by journals.sagepub.com/home/taj 5 Therapeutic Advances in Chronic Disease 12 Figure 3. Inflammasome: Recognition of bacteria, PAMPs, and DAMPs activates the inflammasome through a microbial or damage-sensing protein of the NOD-like receptor family (NLRP3). NLRP3 activates Caspase-1 and cleaves pro-IL-1β yielding its active form. Secreted IL-1β recruits inflammatory cells (mainly neutrophils) and perpetuates the immune response. This process is favored by the presence of genetic mutations in genes that codify proteins involved in inflammasome function, such as NLRP3. mechanical friction leads to release of cellular into its active form.16 Secretion of IL-1β will damage-associated molecular patterns (DAMPs) trigger an uncontrolled activation of innate and penetration of microbial components into immunity, perpetuating the inflammatory activ- the follicles, which become dilated and eventu- ity.43 IL-1β induces the expression of CXCL1 ally rupture.40,41 The release of follicular content and CXCL6 by fibroblasts, and TNF-α induces to the dermis produces a significant inflamma- the expression of CXCL8, CXCL11, CCL2, tory response, primarily mediated by an innate and CCL20 by keratinocytes. These chemokines immune response to the presence of DAMPs, will attract granulocytes, T cells, B cells, and pathogen-associated molecular patterns monocytes; the latter differentiate to mac- (PAMPs), and microbial antigens of the com- rophages (Figure 2).40,4 Fibroblast activation via mensal flora, followed by activation of Th1 and IL-1β also enhances the secretion of a range of Th17 pathways. PAMPs and DAMPs released matrix metalloproteinases (MMPs), IL-32, and to the dermis activate macrophages through IL-6 which implicates massive tissue immune Toll-like receptor (TLR) and induce production cell infiltration, pus formation, and contributes of tumor necrosis factor-alpha (TNF-α) and, via to tissue destruction and fibrosis (Figure 4).44 inflammasome activation, IL-1β (Figure 2).42 The inflammasome (Figure 3) is an intracellular The complement system has recently attracted protein complex located in macrophages and attention in inflammatory cutaneous disorders neutrophils essential for the control of the innate such as HS. The complement pathway, through immune system. Recognition of PAMPs and C3 and C5, produces inflammation, opsoniza- DAMPs activates the inflammasome through a tion, and bacterial lysis. C3a and C5a are strong microbial or damage-sensing protein of the neutrophil activators and recruiters (Figure 2), NOD-like receptor family (NLRP3). NLRP3 suggesting that complement inhibition might be a activates Caspase-1 and processes pro-IL-1β line of action in HS treatment.45,46 High blood 6 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. Figure 4. Advanced stage: Nodule, abscess, and fistula formation. Th1 (IL-12 polarized) cells produce INF- γ that will activate endothelial cells to recruit more inflammatory cells and will stimulate macrophages to produce IL-10, probably as a compensatory anti-inflammatory response. TNF-α, produced by macrophages, dendritic cells, and T lymphocytes, favors the development of Th17 cells, decreases adiponectin (anti- inflammatory hormone) secretion from adipocytes, and increases the expression of matrix metalloproteinases (MMPs). TNF-α contributes in recruiting inflammatory cells, and the massive infiltration will lead to the nodule and abscesses formation (4) and the production of pus. IL-17A and IL-17F stimulate neutrophils and macrophages resulting in an increase of the expression of IL-1β, IL-6, and TNF-α, as well as MMPs. TNF-α, IL-17A, and IL-17F induce keratinocyte proliferation. In turn, keratinocytes produce IL-17C and IL-36, which act in an autocrine manner to further potentiate their activation and proliferation worsening epidermal acanthosis. IL-1β activates fibroblasts and they produce MMPs, which will conduce to fistula formation (5) and fibrosis through extracellular matrix degeneration. IL-17/IL-22 signaling contributes to sinus keratinization. IL-1α, IL-1β, TNF-α, IL-6, IL-17, IL-12, IL-23, and IL-10 have been identified in pus from HS lesions. concentrations of C5a have been found in HS Elevated levels of TNF-α can be found in skin of patients compared with healthy subjects,42 and patients with HS and they correlate with HS sever- reduction of nodules and draining dermal tunnels ity.43 It favors the development of T helper 17 have been observed following C5a inhibition.47 (Th17) cells, decreases adiponectin (anti-inflam- matory hormone) secretion from adipocytes, and Interferon-gamma (IFN-γ) is secreted by Th1 increases the expression of MMPs (Figure 4).42 cells and activates endothelial cells contributing Also, a high expression of mammalian target of to the massive infiltration of inflammatory cells rapamycin gen (mTOR), implicated in cellular perpetuating the immune response (Figure 4). regulation of survival, growth, and proliferation, IFN-γ also activates macrophages to synthesize has been found in lesional skin. mTORC1 is IL-10, which inhibits Th22 cells, thus leading to important for innate and adaptive immunity and a reduction of IL-22 levels. The drop of IL-22 Th17 differentiation; its implication in inflamma- concentration will lessen the production of tory response in HS has been proved after the AMPs.42 observation of a reduction of the expression of mTORC1 in lesional skin after treatment with TNF-α is produced by macrophages and activated adalimumab (ADA) during 6 weeks.48 Anti-TNF- dendritic cells; it has multiple functions in the α treatment has also been shown to decrease circu- innate and adaptive response happening in HS. lating levels of IL-1β, IL-6, IL-8, IL-10, and journals.sagepub.com/home/taj 7 Therapeutic Advances in Chronic Disease 12 IL-17A, proving its effects in innate and adaptive been identified in pus secretion of HS lesions immunity and highlighting its modulatory effect (Figure 4),55 are involved in the pathogenesis of on Th17 activity.49 the disease, and have been therapeutically tar- geted, as discussed below. High serum levels of IL-17A have been found in HS and correlate with the severity of inflamma- Treatment of a multifactorial disease with com- tion.50 IL-17 stimulates neutrophils and mac- plex pathogenesis such as HS is necessarily multi- rophages resulting in an increase of the expression pronged, with treatment algorithms based on of IL-1β, IL-6, and TNF-α, as well as caspases disease severity.41 In mild stages, topical or oral and MMPs in the follicular unit and perilesional antibiotics alone or combined with topical or skin (Figure 4).42 The fundamental role of IL-17 intralesional corticosteroids, and limited surgical isoforms – bridging the innate and adaptive (via or para-surgical interventions, may suffice to con- the IL-23/IL-17 pathway) immune responses – in trol the disease, but as it progresses, combined the pathogenesis of HS is currently well recog- therapy including systemic and surgical nized and has led to the development of clinical approaches is required.41 trials with anti-IL-17 biologic agents. Th17 cells are a lineage of CD4+ T helper cells producing canonical IL-17A and IL-17F as well as other Treatment cytokines; IL-23 produced by dendritic cells has a fundamental role in the commitment and mainte- Topical treatment nance of this polarization (Figure 2). Both IL-17 The role of microbiome in HS has been studied and IL-23 are increased in lesional and perile- for many years and antibiotics are first-line ther- sional HS skin.51,52 apy for HS, but antimicrobial treatment alone is unlikely to control disease activity. Monotherapy IL-12 and IL-23, driving Th1 and Th17 commit- is considered for mild disease, but in advanced ment, are abundantly expressed by macrophages disease, combination with other treatments is infiltrating papillary and reticular dermis,51 and needed.56 Clinical response rates to antibiotics have also been targeted for therapeutic purposes. are difficult to compare and quantify due to the lack of controlled randomized clinical trials The inflammatory components of dermal (RCTs).56 abscesses that form as a consequence of follicular disruption probably contribute to re-epithelializa- Topical clindamycin 1% twice daily for 12 weeks tion and formation of dermal cysts, sinuses, fistu- is considered a first-line treatment for Hurley I–II las, and epithelialized tunnels, which are a stage, supported by two RCTs that showed supe- structural hallmark of severe HS. These epithelial riority to placebo and equality to oral tetracy- structures are immunologically active, contribut- clines.57,58 Recently, an in vitro study evaluated a ing IL-17C and IL-36 to the increased expression topical formulation of nanostructured lipid carri- of proinflammatory cytokines and chemokines.53 ers containing clindamycin and rifampicin. They Their formation is dependent on IL-17/IL-22 observed that this formulation leads to the accu- signaling; furthermore, the Th17 cytokine IL-22 mulation of both antibiotics into the follicle, sug- mediates proinflammatory effects on keratino- gesting that it could be a promising formulation cytes leading to epidermal acanthosis and hyper- for topical treatment.59 There are increasing proliferation (Figure 4).51 These chronic reports of resistant bacterial stains. Knowledge of epithelialized cavities contribute to create a bacterial resistance profile before initiating ther- favorable habitat for biofilm-producing bacteria, apy, choice of combined therapy over monother- which contribute and perpetuate the inflamma- apy, and avoidance of empiric treatments are tory reaction.39 Sinus tracts contain an invasive recommended.60 proliferative gelatinous mass that is attached to the sinus tract epithelium and contains inflamma- Topical resorcinol 15% once daily has been asso- tory cells and cytokines (Figure 4).54 ciated to good clinical response in an open-label study, including 65 patients with Hurley I and II Multiple cytokines, including IL-1α, IL-1β, HS. Overall, 85.2% (52/65) of patients achieved TNF, IL-6, IL-17, IL-12, IL-23, and IL-10, have HiSCR at week 12, and >80% of reduction in 8 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. AN count was observed. The number of sinus statistically significant reduction of mSS, but it tracts remained unchanged, but a significant was greater in the ADA group. A 34% and 60% reduction in the average length and thickness was of patients achieved HiSCR, respectively.71 observed with ultrasonography at week 12.61 A prospective European cohort study that A phase II open-label study is ongoing to evaluate included 218 patients with HS compared efficacy the effect of topical gentian violet as an antiseptic and tolerability of oral tetracycline and a combi- and wound healing therapy in HS nation of rifampicin plus clindamycin. The results (NCT04388163).62 A phase II open-label study showed no significant differences in efficacy with topical LTX-109 aims to evaluate its antimi- between the two treatments, regardless of the dis- crobial and anti-inflammatory effects in HS treat- ease severity.65 ment (NCT04756336). Also, since biofilm contributes to inflammatory response in HS, its The association of daily clindamycin (600– composition and changes after applying a topical 1800 mg, according to weight) and ofloxacin antibiofilm surfactant wound gel are under study (200–400 mg) for a mean observation period of (NCT04648631).63 4.3 months in 65 patients led to a 33.8% (22/65) of complete response and a 24.6% (16/65) of par- Finally, a phase II open-label trial with topical tial response.72 The authors state that the overall ruxolitinib 1.5% cream, a JAK1/JAK2 inhibitor, response rates obtained (58.4) could be compara- is expected to start promptly (NCT04414514).64 ble with the ones achieved with association of rifampicin and clindamycin.56 Systemic treatment Prospective and retrospective cohort studies place Systemic antibiotic treatment. Tetracyclines (tet- antibiotic regimens such as rifampin–moxifloxa- racycline, doxycycline, minocycline, lymecycline) cin–metronidazole combined therapy, iv (intrave- are considered first-line oral treatment for HS nous) ceftriaxone and iv ertapenem (particularly based on clinical experience.10 A recent multi- effective as a rescue treatment) as a third-line center prospective cohort study showed signifi- therapy for severe HS patients.56,73,74 It should be cant decrease in IHS4 from baseline and a 40% of taken into account that HS international alliance HiSCR achievement after 12-week treatment guidelines recommend only one antibiotic of the with tetracycline.65 Likewise, a retrospective study same class should be used for a maximum of comparing the efficacy of lymecycline (300 mg 12 weeks.70 daily) versus the combination therapy clindamycin and rifampicin (600 mg plus 600 mg daily) during Oral retinoids. Oral retinoids have been reported 10 weeks in 52 patients (26 per group) observed a to modulate IL-6 and IFN-γ activity as well as 57.7% and 53.8% HiSCR achievement, exert antiproliferative activity in keratinocytes. respectively.66 However, there is no compelling evidence of their effect in lesional HS skin. Acitretin results in HS Clindamycin and rifampicin used at a dose of are variable (doses ranging from 0.5 to 0.6 mg/ 300 mg twice daily have been proven effective in kg/d and mean duration of 3–12 months), with HS in several observational studies65,67–69 and are response rates close to 50%75 and high recurrence considered a first-line and second-line treatment rates in monotherapy (up to 40% as reported by for HS. A systematic review of retrospective and Puri and Talwar).76 However, good clinical out- prospective series reported response rates from comes have been reported in some series.77 71% to 93% in 187 patients, strongly favoring Acitretin should be considered a second- or third- their use.56 As recommended in international HS line therapy for HS.56 guidelines, systemic clindamycin and rifampicin (dosage: 300 mg twice daily) should be adminis- Isotretinoin has shown discordant results in retro- tered for an average length of 10 weeks in Hurley spective cohort studies and case series.78 Better stage II/III patients presenting with several active responses are reported in mild disease and with lesions.70 A single-center retrospective study low doses (<1 mg/kg/d). Isotretinoin should be compared the efficacy of rifampicin plus clinda- considered as a second- or third-line therapy or in mycin versus ADA. Both treatments achieved a patients with severe concomitant acne.56 journals.sagepub.com/home/taj 9 Therapeutic Advances in Chronic Disease 12 Alitretinoin has been evaluated in a single pro- HS flares.91,92 Intralesional corticosteroids can spective uncontrolled study of 14 women receiv- lead to rapid resolution of inflammatory nod- ing alitretinoin 10 mg/kg/d for 24 weeks. Overall, ules.91,93 In a multicenter retrospective study, 78.5% of patients were reported to experience complete resolution of inflammatory and non- significant clinical improvement as assessed by inflammatory lesions was observed in 95 lesions mSS.79 (70.37%) treated with intralesional corticoste- roids (at variable dilutions and volumes).94 An RCTs would be required in order to evaluate the interventional prospective study evaluated the real efficacy of oral retinoids, in as much as there efficacy of intralesional ultrasound-guided injec- are no studies comparing acitretin with tions of triamcinolone plus lincomycin, at base- isotretinoin. line and after 2 weeks; clinical and symptomatic improvement was observed in 36 out of 37 Hormonal treatment. Perimenstrual exacerba- patients at week 4.95 However, the only RCT con- tions, rare postmenopausal occurrence, and ducted with two different doses of intralesional improvement during pregnancy suggest that an triamcinolone (10 and 40 mg/ml) showed no sta- endocrine influence for the disease,80 but no rela- tistical differences with placebo (intralesional tionship to serum and tissue hormone levels, has normal saline).96 Comparing the results of differ- been found.81 Patients with polycystic ovarian ent studies is difficult due to the diversity of dos- syndrome and HS may benefit from hormonal ages and volumes used. It is not clear which is the therapy, either alone as monotherapy in mild-to- most effective concentration.97 An ongoing phase moderate HS or in combination therapy for more IV RCT including 200 patients aims to evaluate severe disease.56 RCTs are needed to define the three different dosages of intralesional triamcino- role of hormonal treatment as an alternative or lone (10, 20, and 40 mg/ml) and find the optimal concomitant therapy together with antibiotics or posology (NCT04582669).98 biologics.82 An RCT compared ethinylestradiol/ noregestrel with ethinylestradiol and cyproterone High dose and protracted treatment with oral acetate, both showing satisfactory clinical corticosteroids are not recommended since HS response.83 rapidly flares after tapering, but low-dose sys- temic prednisolone can be a valuable adjunct Spironolactone 100 to 150 mg daily is also used.56 therapy for recalcitrant HS.99 American guide- Recently, some reports have been published on lines recommend the use of prednisone pulses or the benefits of metformin in HS, which have been multiweek tapers starting at 0.5 to 1 mg/kg daily attributed to its anti-androgen and anti-inflam- as rescue therapy for flares or as a bridge to other matory effects.82,84 A phase III RCT with 65 long-term therapy; the effect is rapid and substan- patients is being conducted in order to evaluate tial, but side effects limit their prolonged use.56 the efficacy of metformin plus doxycycline versus doxycycline in monotherapy (NCT04649502).85 Surgery Finasteride is a selective competitive inhibitor of Recommendations for the surgical management type II 5-α reductase. Improvement of moderate- of acute HS lesions rely on low-quality, uncon- to-severe HS has been occasionally reported, but trolled, retrospective reports. Incision and drain- recurrences followed treatment cessation.86 In a age of acute lesions provide a rapid relief of the preliminary trial, clinical response was observed symptoms, but recurrence rates are close to in six out of seven patients receiving finasteride 100%.100 Deroofing, with lower recurrence rates (5 mg/d) as monotherapy after 8–24 months of (20–40%), is adequate to treat localized lesions or treatment.87 Finasteride has also been proposed all the lesions of one anatomical site in Hurley as an alternative treatment in pediatric HS with I–II stage.101 Limited local excision consists in the appropriate tolerance and clinical response in a excision of separate lesions with surgical margins; case series.88,89 it is indicated for Hurley I–II HS and has similar recurrence rates to deroofing.101,102 Combination Oral and intralesional corticosterds. Oral cortico- of deroofing with subsequent sinus tract excision steroids can produce pan-cytokine inhibition,90 enhances clinical results and decreases recurrence which agrees with the reported efficacy of sys- rates.103 Wide excision is indicated for Hurley II– temic and intralesional corticosteroids in acute III HS and consists in the excision of large areas 10 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. of involved skin with wide margins.102 This tech- laser diode (400 nm).106 Response rates are not nique is associated with lower recurrence rates.100 comparable between studies, but intralesional The reconstruction strategy chosen after wide PDT seems to determine better outcomes and excision determines recurrence rates: 22% with the axillary region has better response rates.112 primary closure, 11% with secondary intention healing, 2% with skin graft, and 2% with fascio- Photobiomodulation is also a useful tool for non- cutaneous flaps.104 Location of lesions can also invasive treatment of HS. It has been reported to predict clinical outcomes: perianal, vulvar, and have beneficial effects on promoting wound heal- inferior breast excisions have higher recurrence ing, angiogenesis, vasodilation, and relieving from rates.9 pain and inflammation in an in-vitro model mim- icking HS disease. It has been proposed as an Prior medical treatment can improve surgical out- adjuvant third-line treatment for the management comes. Combination surgery with biologic treat- of HS.113 ment has demonstrated higher rates of cure.105 Laser therapy. Laser and photodynamic therapy Targeted biologic therapy (PDT) have been used alone and in combination Table 4 summarizes the above-mentioned studies with other therapies with variable results.106 Com- of biologic therapies. parison between treatment modalities is challeng- ing because there are no standardized treatment Anti-TNF-α agents. Adalimumab. ADA is a fully protocols using these devices and settings vary human monoclonal antibody targeting soluble between machines. Larger randomized controlled and transmembrane TNF-α. It is the only biologic trials are needed to elucidate their role and deter- approved for the treatment of moderate-to-severe mine the optimal treatment settings.107 HS in adults and adolescents by the US Food and Drug Administration (FDA) and European Medi- Long-pulsed neodymium-doped yttrium alu- cines Agency (EMA), based on the results of two minum garnet (Nd:YAG) laser (1064 nm) has phase III trials (PIONEER I and PIONEER II).114 shown clinical improvement108 and diminution of These double-blind, placebo-controlled studies inflammation in tissue biopsy specimens.108 enrolled 633 patients who received subcutaneous Carbon dioxide (CO2) laser (10,600 nm) has (sc) ADA 160 mg at week 0, 80 mg at week 2, and been used in combination with Nd:YAG or 40 mg weekly starting at week 4, or placebo. In alone.107 CO2 laser (fractional mode) used before PIONEER II, patients were permitted to continue Nd:YAG enhances the depth of penetration of treatment with antibiotics (tetracyclines) in stable the latter.109 Ablative CO2 laser can be used to doses.104 The HiSCR with ADA was higher than perform sinus deroofing or ablative destruction of with placebo at week 12 (50.6% versus 26.8%, lesions,110 and is useful in treating anesthetic scars p < 0.001, pooled efficacy from trials PIONEER I or contractures of chronic scars.107 Alexandrite and II).115 The Dermatology Life Quality Index laser has shown promising results in case reports (DLQI) score was also improved,115–117 and ADA and case series.107 An ongoing open-label study was well tolerated with the expected adverse event aims to evaluate the efficacy of Alexandrite hair (AE) profile.115 Among the 88 patients who removal laser in 20 patients with bilateral disease entered an open-label extension (OLE) study with (axilla or groin). One side will be treated and the ADA 40 mg weekly, HiSCR rates were 62.5% at other one will serve as control (NCT03054155).111 week 36 and 52.3% at week 168.116 ADA also reduced number and duration of flares, and PDT has been associated with good clinical out- lengthened flare-free intervals both in short- and comes in several studies. The photosensitizers long-term follow-up.118,119 used in different concentrations include 5-ami- nolevulinic acid (ALA), methyl aminolevulinate Real-life data provided in a retrospective, multi- (MAL), and methylene blue (MB). PDT has center cohort study showed ADA efficacy/safety been performed following either topical (ALA, and an inverse correlation between therapeutic MAL, and MB) or intralesional (ALA and MB) delay and clinical response, supporting early ADA application of the photosensitizing agent. Light use and providing evidence for a ‘window of sources also vary, including red light (635 nm), opportunity’ in HS treatment.120 Real-life data blue light, Intense Pulsed Light (630 nm), and provided in a retrospective cross-sectional study journals.sagepub.com/home/taj 11 12 Table 4. Biologic treatments for hidradenitis suppurativa. Molecule Drug Study type Dose Results Reference TNF-α Adalimumab Phase III placebo- 160 mg sc at week 0, 80 mg at week 2, and Percentage of patients achieving HiSCR versus Kimball et al.115 controlled RCT 40 mg weekly starting at week 4 placebo at week 12: 41.8% versus 26.0%, p = 0.003 (PIONEER I) (n = 154) Phase III placebo- 160 mg sc at week 0, 80 mg at week 2, and Percentage of patients achieving HiSCR versus Kimball et al.115 controlled RCT 40 mg weekly starting at week 4 placebo at week 12: 58.9% versus 27.6%, p < 0.001 (PIONEER II) Therapeutic Advances in Chronic Disease 12 (n = 153) Open-label 40 mg sc every week continuously Percentage of patients achieving HiSCR: 62.5% at Zouboulis et al.116 extension of phase (168 weeks) week 36 and 52.3% at week 168 III PIONEER I and III (n = 88) Retrospective real- 160 mg sc at week 0, 80 mg at week 2, and Percentage of patients improving HS-PGA score: Muralidharan et al.121 life cohort study 40 mg weekly starting at week 4 77% (n = 101) Retrospective, 160 mg sc at week 0, 80 mg at week 2, and Percentage of patients achieving HiSCR: 43.7% at Marzano et al.120 real-life 40 mg weekly starting at week 4 week 16 and 53.9% at week 52 multicenter cohort study (n = 389) IFX Phase II placebo- 5 mg/kg iv at weeks 0, 2, 4, 6, 14, and 22 Percentage of patients with >50% of decrease of Grant et al.126 controlled, double- HSSI index at week 8 versus placebo: 27% versus blind RCT (n = 38) 5% (p = 0.092) Prospective open- 7.5 mg/kg iv at weeks 0, 2, and 6, then Percentage of patients achieving HS-PGA 0–2: Ghias et al.128 label study (n = 42) 7.5 mg/kg every 4 weeks. Dose escalation IFX 7.5: 47.6% at week 4 and 70.8% at week 12 to 10 mg/kg considered after induction IFX 10: 37.5% at week 4 and 50% at week 12 dose if HS-PGA score ⩾3 Certolizumab Retrospective study 200 mg sc every 2 weeks Unsuccessful response with low-dosage Sand and Thomsen,132 Tampouratzi et al.,133 pegol and case reports 400 mg every 2 weeks certolizumab Holm et al.,134 Esme et al.,135 Wohlmuth- (n = 6) Satisfactory response to certolizumab in four case Wieser and Alhusayen136 reports Etanercept Phase II open- 50 mg sc weekly HS-PGA at baseline versus week 12: 4.35 versus Lee et al.138 label, single-arm 3.5 (p = 0.14) RCT (n = 15) Percentage of patients improving HS-PGA: 20%; 95% CI: 4.3–48.1 Golimumab Case reports (n = 2) 50 mg sc every 4 weeks van der Zee et al.,139 Tursi140 200 mg sc at week 0 and 100 mg every 4 weeks journals.sagepub.com/home/taj (Continued) Table 4. (Continued) Molecule Drug Study type Dose Results Reference IL-17 Secukinumab Open-label, single- 300 mg sc weekly for 5 weeks, then every Percentage of patients achieving HiSCR at week Prussick et al.141 arm, pilot trial 4 weeks 24: 67% (n = 9) journals.sagepub.com/home/taj Open-label, single- 300 mg sc weekly for 5 weeks, then 9 Percentage of patients achieving HiSCR at week Casseres et al.142 arm pilot trial patients received 300 mg every 4 weeks, 24: 70% included (n = 20) and 11 patients received 300 mg every 2 weeks Phase III RCTs Pending Novartis Pharmaceuticals146–148 NCT03713632, NCT03713619, NCT04179175 Brodalumab Open-label cohort 210 mg sc at weeks 0, 1, and 2, then Percentage of patients achieving HiSCR at week Frew et al.152 study (n = 10) 210 mg every 2 weeks 12: 100% Open-label cohort 210 mg sc weekly Percentage of patients achieving HiSCR at week Frew et al.153 study (n = 10) 12: 100% Bimekizumab Phase II placebo- 640 mg sc at week 0 and 320 mg every Percentage of patients achieving HiSCR versus Glatt et al.155 controlled, double- 2 weeks placebo at week 12: 57.3% versus 26.1% (95% blind RCT (n = 90) CI, 11.0%–50.4%; posterior probability of superiority = 0.998) Phase III placebo- Pending UCB Biopharma SRL156,157 controlled RCT (NCT04242446, NCT04242498) Ixekizumab Case reports (n = 3) 160 mg sc at week 0; 80 mg at weeks 2, 4, Satisfactory response to ixekizumab in three case Odorici et al.,158 Megna et al.,159 Reardon 6, 8, 10, and 12; and 80 mg every 4 weeks reports et al.160 CJM112 Phase II placebo- 300 mg sc weekly for 5 weeks followed by HS-PGA response rate versus placebo at week 16: Novartis Pharmaceuticals,162 Kimball controlled, 300 mg every 2 weeks 32.3% versus 12.5% (p = 0.9729) et al.163 double-blind RCT (NCT02421172) (n = 66) IL-12/23 Ustekinumab Phase II open-label 45 mg sc if <90 kg and 90 mg if >90 kg at Percentage of patients achieving HiSCR at week Blok et al.164 study (n = 17) weeks 0, 4, 16, and 28 40: 47% (Continued) 13 V Amat-Samaranch, E Agut-Busquet et al. 14 Table 4. (Continued) Molecule Drug Study type Dose Results Reference Case reports and sc weight adjusted dose Variable response to ustekinumab Gulliver et al.,165 Sharon et al.,166 Santos- case series (n = 30) 90 mg sc every 12 weeks Pérez et al.,167 Eisen,168 Scholl et al.,169 90 mg sc every 8 weeks Takeda et al.,170 Cline and Pichardo,171 Montero-Vilchez et al.,172 Valenzuela-Ubiña et al.175 Retrospective iv weight adjusted dose (⩽55 kg, 260 mg; Percentage of patients achieving HiSCR at week Romaní et al.173 Therapeutic Advances in Chronic Disease 12 multicenter study 56–85 kg, 390 mg; ⩾86 kg, 520 mg), 16: 50% (n = 14) followed by 90 mg sc every 8 weeks Retrospective iv weight adjusted dose, followed by 90 mg Percentage of patients achieving HiSCR at week Sánchez-Martínez et al.174 unicenter study sc every 8 weeks 16: 50% (n = 14) IL-23 Guselkumab Phase II placebo- Pending Janssen Research & Development, LLC183 controlled, double-blind RCT (NCT03628924) Case reports and 100 mg sc at weeks 0, 4, and then every Variable response to guselkumab Kovacs and Podda,176 Casseres et al.,177 case series (n = 19) 8 weeks Kearney et al.,178 Berman et al.,179 100 mg sc at weeks 0, 4, and then every Jørgensen et al.,180 Burzi et al.,181 Montero- 4 weeks Vilchez et al.182 Risankizumab Case reports (n = 4) 150 mg sc at weeks 0 and 4, followed by Successful response, HiSCR achievement Marques et al.,184 Licata et al.,185 Caposiena 150 mg sc every 12 weeks Caro et al.186 Phase II placebo- Pending AbbVie187 controlled, double-blind RCT (NCT03926169) Tildrakizumab Case series (n = 5) 100 mg sc at weeks 0, 4, and 200 mg every All patients showed improvement in AN count at Kok et al.188 4 weeks thereafter week 8 IL-1 Anakinra Open-label phase II 100 mg sc daily for 8 weeks Mean decrease of 34.8 points in mSS. All patients Leslie et al.189 study (n = 6) experienced a rebound during an 8-week follow-up period Phase II placebo- 100 mg sc daily for 12 weeks Percentage of patients achieving HiSCR versus Tzanetakou et al.190 controlled, double- placebo at week 12: 78% versus 30% (p = 0.04) blind RCT (n = 20) After a 12-week observation period, the HiSCR difference between groups was not significant (Continued) journals.sagepub.com/home/taj Table 4. (Continued) Molecule Drug Study type Dose Results Reference Bermkimab Phase II placebo- 7.5 mg/kg iv every 2 weeks Percentage of patients achieving HiSCR versus Kanni et al.196 controlled, placebo at week 12: 60% versus 10% (p = 0.035) double-blind RCT (NCT02643654) (n = 10) Open-label 7.5 mg/kg iv every 2 weeks (patients who Percentage of patients achieving HiSCR at week Kanni et al.197 journals.sagepub.com/home/taj extension of had been randomized in the placebo 12: 75% NCT02643654 (n = 8) group) Phase II 400 mg sc weekly Percentage of patients achieving HiSCR at week Gottlieb et al.198 multicenter open- 12: 61% of anti-TNF naïve patients and 63% of label study (n = 42) anti-TNF failure patients Canakinumab Case reports (n = 6) 150 mg sc at day 1, then monthly Variable results. Positive results in three patients. Houriet et al.,200 Jaeger et al.,201 Sun et al.,202 150 mg sc at day 1, day 15, then monthly Negative results in three patients (two of them Tekin et al.203 150 mg every week/4 weeks/8 weeks with concomitant pyoderma gangrenosum) PDE-4 Apremilast Phase II placebo- 30 mg po twice daily Percentage of patients achieving HiSCR versus Vossen et al.204 inhibitors controlled, double- placebo at week 16: 53.3% versus 0% (p = 0.055) blind RCT (n = 20) Investigator- 30 mg po twice daily Absence of significant changes in inflammatory Vossen et al.206 initiated trial, markers in lesional skin of patients receiving placebo controlled apremilast compared with placebo, despite clinical (n = 15) improvement in the apremilast group Complement IFX-1 Phase II open-label 800 mg iv on days 1, 4, 8, 15, 22, 29, 36, Percentage of patients achieving HiSCR at day 43: Giamarellos-Bourboulis et al.47 C5a trial (n = 12) and 43 75% inhibitors Percentage of patients achieving HiSCR after the 3-month follow-up period: 83% Phase II placebo- 400 mg iv every 4 weeks Percentage of patients achieving HiSCR, InflaRx GmbH207 controlled, 800 mg every 4 weeks respectively: 47.1%, 40.4%, 51.5%, 38.7%, and double-blind RCT 800 mg every 2 weeks 45.5% (NCT03487276) 1200 mg every 2 weeks (n = 175) Placebo Avacopan Phase II placebo- Pending ChemoCentryx,208 Sarin209 controlled, double-blind RCT (NCT03852472) Ex vivo study (NCT04251663) JAK Tofacitinib Case report (n = 2) Clinical improvement Savage et al.210 inhibitors (Continued) 15 V Amat-Samaranch, E Agut-Busquet et al. 16 Table 4. (Continued) Molecule Drug Study type Dose Results Reference INCB054707 Phase II placebo- Pending Incyte Corporation213 controlled, double-blind RCT (NCT04476043) Therapeutic Advances in Chronic Disease 12 Upadacitinib Phase II placebo- Pending AbbVie214 controlled, double-blind RCT (NCT04430855) Other Iscalimab Phase II placebo- Pending Novartis Pharmaceuticals215 molecules (anti-CD40) controlled, double-blind RCT (NCT03827798) Spesolimab Phase II placebo- Pending Boehringer Ingelheim216 (anti-IL36) controlled, double-blind RCT (NCT04762277) Ismidolimab Phase II placebo- Pending AnaptysBio, Inc.217 (anti-IL36) controlled, double-blind RCT (NCT04856930) LY 3041658 Phase II placebo- Pending Eli Lilly and Company218 (anti-CXCR1 controlled, and CXCR2 double-blind RCT signaling) (NCT04493502) LYS 006 (LTA4 Phase II placebo- Pending Novartis Pharmaceuticals215,219 hydrolase controlled, inhibitor) double-blind RCTs (NCT03827798, NCT03497897) KT-474 First-in-human Pending Kymera Therapeutics, Inc.220 study (phase I) (NCT04772885) sc, subcutanepus; po, oral; AN, abscess and nodule; CI, confidence interval; HiSCR, Hidradenitis Suppurativa Clinical Response; HS-PGA, Hidradenitis Suppurativa Physician’s Global Assessment; HSSI, Hidradenitis Suppurativa Severity Index; IFX, infliximab; LTA4, leukotriene A4; PDE-4, phosphodiesterase–4; RCT, randomized clinical trial. journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. showed efficacy rates and improvement in DLQI In a recent retrospective cohort study, the efficacy rates comparable with previous trials.121 of IFX versus its biosimilar infliximab-abda has been found to be clinically equivalent (HiSCR ADA 40 mg weekly is more effective and offers 71% versus 60% at week 10, p = 0.47).130 more prevention of flaring than 40 mg every other week122 and may be continued indefinitely.116 In a practice cohort study, drug survivals of ADA Dose intensification to 80 mg weekly has been and IFX in HS have been found to be similar and proposed for patients with insufficient response rather low (30.5% and 48.6% at 24 months); or with loss of efficacy after initial response to treatment interruption was predominantly deter- 40 mg/week, but larger studies are required to mined by ineffectiveness and side-effects.131 corroborate this observation.123 Certolizumab pegol. Certolizumab pegol (CZP) is Biosimilar ADA (SB5) has also been found to be a pegylated humanized monoclonal antigen-bind- effective, well tolerated, and interchangeable with ing fragment of IgG, which binds to TNF-α. A originator ADA for HS treatment in a retrospec- retrospective study on off-label use of TNF- tive 36 weeks ‘real life’ observational study.124 inhibitors reported no efficacy of low-dose CZP (200 mg every 2 weeks) in two patients.132 Several Calprotectin, fractalkine, and HCC-4 have been case reports purport successful results of CZP identified as potential predictive biomarkers of 400 mg sc every 2 weeks133–136 in patients with ADA response (86% predictive accuracy rate for moderate to HS refractory to other biologics. ADA response).125 Unlike other anti-TNF-α agents, CZP is not sub- The superior response to TNF-α blockade of ject to active placental transfer and would be ido- subcutaneous nodules versus tunnels suggests that neous for the treatment of pregnant patients.137 the formation of the latter is mediated by IL-17 To date, there is only one report of successful rather than by TNF-α signaling.53 treatment of HS with CZP during pregnancy in a patient with Hurley stage III HS.136 Infliximab. Infliximab (IFX) is a chimeric monoclo- nal antibody targeting soluble and transmembrane Other TNF-α inhibitory agents. Etanercept is a TNF-α.114 In a phase II randomized, double-blind recombinant human TNF-α receptor p75-Fc study, 38 patients with moderate-to-severe HS fusion protein that competitively binds mem- received 5 mg/kg of iv IFX on weeks 0, 2, 4, 6, 14, brane-bound TNF-α receptors. Only one phase and 22. At week 8, 57% of patients had a < 50% II open-label, single-arm RCT of etanercept has decrease of HSSI vs. 5% in the placebo group (p = been conducted, with no significant improvement 0.092). A post-hoc analysis showed that 60% of in patient- or physician-reported outcomes.138 patients had a 25% to <50% decrease in HS HSSI compared with 5.6% of patients receiving placebo Golimumab is a fully human anti-TNF-α mono- (p < 0.001).126 IFX also reduced inflammatory clonal antibody that binds to soluble and mem- markers as well as improved mean DLQI and vis- brane-bound TNF-α. Two case reports of ual analog scores (VAS) of pain.126 The drug was golimumab treatment with HS have been pub- well tolerated, and no safety issues were reported.126 lished;139,140 it was successful only in one patient with concomitant pyostomatitis vegetans and silent Doses higher than 5 mg/kg have been proposed. ulcerative colitis who was treated with golimumab Oskardmay et al.127 conducted a retrospective 200 mg followed by 100 mg every 4 weeks.140 cohort study with 52 patients treated with IFX 10 mg/kg every 6 or 8 weeks, obtaining satisfac- Anti-IL-17 agents. Serum levels of IL-17 have tory results. Also, a prospective study concluded been found to be elevated in patients with HS that starting IFX at 7.5 mg every 4 weeks, with compared with healthy controls, and to correlate possible dose escalation to 10 mg, provides opti- with disease severity according to the Hurley mal control of disease activity.128 New prospec- stage.50 This has led to investigate new therapeu- tive placebo- or active-agent-controlled phase III tic strategies, even though the relative contribu- trials should be done to ascertain the eventual tions of the different isoforms of IL-17 (A, F, C, role of IFX in HS treatment.129 etc.) have not been completely elucidated. journals.sagepub.com/home/taj 17 Therapeutic Advances in Chronic Disease 12 Secukinumab. Secukinumab (SEC) is a human BRO has shown promising results in three case monoclonal immunoglobulin G1 kappa antibody reports,133,150,151 and two phase I open-label trials that selectively binds to IL-17A. An open-label have been conducted. An open-label cohort pilot trial included nine patients with moderate- study included 10 patients with moderate-to- to-severe HS who were administered SEC 300 mg severe HS who were treated with BRO 210 mg sc sc weekly for 5 weeks, then every 4 weeks for at weeks 0, 1, and 2 and every 2 weeks thereafter 24 weeks; 67% (6/9) of patients achieved until week 24. At week 12, all patients (10/10) HiSCR.141 achieved HiSCR (as early as week 2 in some), and 80% achieved IHS4 category change. The A single-arm, open-label pilot trial included 20 HS authors highlighted the rapid reduction of tunnel patients, Hurley grades II–III, who received SEC drainage and ultrasonographical signs of inflam- 300 mg weekly for 5 weeks; then 9 patients were mation, usually refractory to other therapies.152 administered SEC 300 mg every 4 weeks, and 11 However, two patients with extensive gluteal patients were treated with 300 mg every 2 weeks tunnels experienced relapses of drainage 1 week through week 24. Seventy percent (14/20) of all after each drug administration during the main- patients achieved HiSCR by week 24.142 tenance period (210 mg every 2 weeks). Thus, a subset of patients with severe disease and high Similar results of the same protocol were observed proportion of sinus tracts might require higher in a retrospective study evaluating 20 Hurley IC doses of BRO.152 This hypothesis was evaluated - III HS patients previously refractory to antibiot- in another open-label study including 10 patients ics and anti-TNF-α (ADA or IFX): after 16 weeks, with draining tunnels and severe HS. BRO 75% (15/29) of patients achieved HiSCR and the 210 mg weekly was administered for 24 weeks response was maintained for an average of with good tolerance and safety profile. At week 14 months.143 In two patients who developed 12, 100% of patients achieved HiSCR, 80% Crohn’s disease during treatment, the drug was achieved a 75% reduction in total AN count stopped and they were successfully treated with (HiSCR-75), and 50% achieved a 100% reduc- ustekinumab (UST) and IFX, respectively.143 tion (HiSCR-100). In contrast to the every There is some concern about the risk of develop- 2-week dosing, cyclical disease suppression or ing IBD with anti-IL-17 treatment in HS patients, recurrence in tunnel drainage was not observed who are already at higher risk of IBD.144 In a with weekly dosing.153 recent Italian retrospective study of HS patients treated with psoriasis dosage of SEC, 13/31 The efficacy of BRO in reducing drainage of sinus (41%) of patients achieved HiSCR at week 28, tracts is remarkable, since other therapies have and there was no report of IBD triggering or been proven unsuccessful;152 blockade of worsening.145 keratinocyte-derived IL-17C might provide a potential explanation. Three phase III RCTs of SEC for the treatment of HS are currently ongoing (NCT03713632, Other anti-IL-17 agents. Bimekizumab is an NCT03713619, NCT04179175).146–148 humanized monoclonal antibody that potently and selectively neutralizes IL-17A and IL-17F.154 SEC has been reported to induce HS in a patient A phase II RCT comparing bimekizumab with with psoriasis, probably due to cytokine imbal- placebo including 90 patients has been recently ance after treatment initiation.149 published. Bimekizumab 640 mg was adminis- tered subcutaneously at week 0 and then 320 mg Brodalumab. Brodalumab (BRO) is a monoclonal every 2 weeks during 10 weeks. At week 12, antibody that binds to the IL-17RA subunit of the HiSCR was achieved in a 57.3% of patients in the IL-17 receptor dimer and blocks signaling of mul- bimekizumab group and 26.1% in the placebo tiple isoforms of IL-17 (mostly IL-17A, IL-17C, group (95% credible interval for difference, 11.0– and IL-17F). This may be important as each of 50.4%; posterior probability of superior- these cytokines can drive neutrophilic inflamma- ity = 0.998).155 Two phase III RCTs are being tion, and the blockade of multiple isoforms might conducted to evaluate the efficacy and safety of provide superior results to blockade of individual bimekizumab for HS treatment (NCT04242446, cytokines. NCT04242498).156,157 18 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. Ixekizumab is a humanized IgG4-type monoclo- A retrospective multicenter study evaluated HS nal antibody that binds with high affinity to solu- treatment with iv infusions of UST adjusted by ble IL-17A and IL-17 A/F. There is scarce weight (⩽55 kg, 260 mg; 56–85 kg, 390 mg; evidence of the efficacy of this drug for HS treat- ⩾86 kg, 520 mg), followed by subcutaneous ment; our literature review only found three maintenance dose of 90 mg every 8 weeks (the recent case reports suggesting the potential use- regime approved for Crohn’s disease) in 14 fulness of ixekizumab for HS.158–160 patients. Included patients had recalcitrant HS that had not responded to at least one prior bio- CJM112 is a novel fully human anti-IL-17A logic treatment. At 16 weeks, 50% of patients IgG1/κ monoclonal antibody that binds with sim- achieved HiSCR and a significant improvement ilar affinity as ixekizumab to both human IL-17A of DLQI was reported in over 70% of patients.173 and IL-17A/F.161 A phase II RCT multicenter A retrospective study including six patients study in patients with moderate-to-severe HS has treated with this regime obtained the same clini- been completed to determine the efficacy and cal response.174 Moreover, in a retrospective safety of multiple doses of CJM112 study, HiSCR was achieved by 9/10 patients (NCT02421172).162 At 16 weeks, the HS-PGA treated with UST 90 mg every 8 weeks (without response rate was 32.3% (10/31) with CJM112, induction dose).175 Whether higher doses are which was significantly superior to 12.5% (4/32) more effective in HS requires further evaluation with placebo. The decrease in number of inflam- in RCTs. matory lesions (abscesses, nodules, and fistulas) was 56% with CJM112 compared with 30% for Anti-IL-23 agents. Guselkumab. Guselkumab placebo.163 (GUS) is a human monoclonal antibody that targets the p19 protein subunit of extracellular Anti-IL-12/23 agents. UST. UST is a human IL-23. Six published case reports and retro- IgG1K monoclonal antibody that binds with high spective case series have reported positive affinity to the p40 subunit of IL-12 and IL-23. results treating recalcitrant HS with GUS These cytokines are thereby prevented from inter- 100 mg sc at weeks 0, 4, and then every acting with their IL-12Rb1 receptor protein, 8 weeks.176–181 A case series reported poor which is expressed on the surface of T cells and results with higher doses of GUS (100 mg at natural killer cells.114 Certain genetic variations weeks 0, 4, and then every 4 weeks): discrete within the gene encoding the common IL-12bR1 improvement in two patients, no response in subunit of the IL-12/IL-23 receptor have been one patient, and worsening in one patient.182 shown to be associated with a more severe course These variable results might be explained of HS.164 because most patients have severe disease refractory to other biologic therapies. One phase II open-label study evaluated the effi- cacy of UST, as measured by mSS, in 17 patients A phase II randomized, placebo-controlled, dou- with moderate-to-severe HS. The weight-based ble-blind study evaluating the efficacy, safety, and psoriasis dosage of UST was used at weeks 0, 4, 16, tolerability of three different dosages of GUS in and 28, followed by an observation period until patients with moderate-to-severe HS has been week 40. At week 40, improvement of mSS was completed, but its results have not yet been pub- marked in 35% of patients and moderate in 47%. A lished (NCT03628924).183 47% of patients achieved HiSCR at week 40. Although the authors compared these results with Other anti-IL-23 agents. Risankizumab is a human- those obtained in ADA RCTs, the high dropout ized immunoglobulin G1 monoclonal antibody rate in their study carries a significant risk of bias.164 selective to the IL-23. Three publications report clinical response to risankizumab in four patients Response rates to UST have been variable in sev- treated at psoriasis doses (150 mg sc at week 0, eral case reports and small series.165–172 As in the week 4, and every 12 weeks thereafter).184–186 A study conducted by Blok et al.,164 psoriasis dos- phase II, double-blind RCT to evaluate the safety ages have been used in most cases, but it is and efficacy of two dose levels of risankizumab in believed that higher doses (like those in Crohn’s adult patients with moderate-to-severe HS is disease) might be necessary to control HS.164 being conducted (NCT03926169).187 journals.sagepub.com/home/taj 19 Therapeutic Advances in Chronic Disease 12 Tildrakizumab is a humanized monoclonal anti- open-label i.v. BER and 75% achieved HiSCR at body that targets the p19 subunit of IL-23. Only week 12 of the OLE period.197 a case series reports a successful clinical response in five patients receiving tildrakizumab 100 mg sc An open-label phase II study evaluated the effi- at weeks 0, 4, and 200 mg every 4 weeks thereaf- cacy of weekly BER 400 mg sc in patients with ter. All patients demonstrated an improvement in moderate-to-severe HS who were naïve (18 AN count at week 8 compared with baseline and patients) or had failed to anti-TNF therapy (23 four patients reported improvement in DLQI.188 patients). A 61% of anti-TNF naïve and 63% of anti-TNF failure patients achieved HiSCR at Anti-IL-1 agents. Anakinra. Anakinra is a recombi- week 12. There was also a significant reduction in nant form of human IL-1 receptor antagonist (IL- AN count [60% (p < 0.004) and 46% (p < 0.001)] 1RA), and it competitively inhibits the interaction and VAS pain score [64% (p < 0.001) and 54% of both IL-1α and IL-1β with their receptor. (p < 0.001)] in anti-TNF naïve and in anti-TNF failure group, respectively, with no drug-related The efficacy of anakinra in the literature remains AEs with the exception of injection site controversial. An open-label phase II trial includ- reactions.198 ing six patients with moderate-to-severe HS treated with daily anakinra 100 mg sc for 8 weeks BER seems a promising first-line biologic treat- demonstrated a significant mean decrease of ment option for refractory moderate-to-severe 34.8 points in mSS and improvement of DLQI in HS as well as a second-line alternative for patients five patients, but post-treatment rebound was with failure to anti-TNF agents.199 observed in all patients during an 8-week follow- up period.189 Moreover, in an RCT including 20 Canakinumab. Canakinumab is a human IgGκ patients with Hurley stage II or III, HiSCR rate monoclonal antibody targeting IL-1β and has was 78% in patients receiving anakinra versus shown positive200,201 and negative202,203 results in 30% in the placebo arm at week 12 (p = 0.04). terms of efficacy in case reports; no RCTs are reg- However, after a 12-week post-treatment obser- istered in www.clinicaltrials.gov. vation period, the HiSCR difference between groups was not significant.190 Long-term efficacy Apremilast. Apremilast (APR) is an oral selective and safety of anakinra was suggested in a small phosphodiesterase–4 (PDE-4) inhibitor. In a series of three patients with follow-up ranging phase II RCT, 8/15 patients (53.3%) receiving from 6 months to 7 years, but all of them eventu- APR 30 mg twice daily for 16 weeks achieved ally relapsed and required a treatment switch to HiSCR compared with 0% in the placebo group anti-TNF.191 Additional case reports and case (p = 0.055).204 Four of the responders continued series alternate success192,193 with failure.139,194,195 APR therapy, with maintenance of response after 2 years of treatment.205 These findings contrast Although the IL-1 pathway has been shown to be with those in an investigator-initiated trial that upregulated in HS,44 the available evidence on did not detect statistically significant changes in anakinra together with frequent injection site inflammatory markers in lesional skin of HS reactions189 make it less attractive than other patients receiving APR compared with placebo, potential therapeutic alternatives. despite clinical improvement in the APR group.206 Bermekimab. Bermekimab (BER), also known as Complement C5a inhibitors. IFX-1 is a monoclo- MABp1, is a recombinant human IgG1 monoclo- nal IgG4 kappa antibody that selectively binds to nal antibody that neutralizes IL-1α by binding it C5a and blocks its biological activity. In a phase II with high affinity. High concentrations of IL-1α open-label trial, administration of IFX-1 800 mg in lesional skin190 provide the basis for clinical iv on days 1, 4, 8, 15, 22, 29, 36, 43, and 50 was development of BER as an HS treatment. performed. Nine out of 12 patients (75%) Intravenous BER (7.5 mg/kg every 2 weeks) achieved HiSCR at the end of treatment and resulted in 60% of patients (6/10) achieving 10/12 (83.3%) at the end of the 3-month follow- HiSCR versus 10% of patients (1/10) in the pla- up period.47 A phase II randomized placebo-con- cebo group at 12 weeks.196 Eight patients who had trolled trial (NCT03487276) has been recently received placebo were then transitioned to completed and has avaliable results. In total, 175 20 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. patients were randomized to receive double-blind diseases characterized by neutrophilic infiltration, treatment with placebo or four different doses of is also being tested in HS patients IFX-1 (400 mg every 4 weeks, 800 mg every (NCT04762277).216 4 weeks, 800 mg every 2 weeks, and 1200 mg every 2 weeks). HiSCR achievement was achieved in Ismidolimab (ANB019) is a monoclonal antibody 47.1%, 40.4%, 51.5%, 38.7%, and 45.5%, directed against the IL-36 receptor, with a phase respectively.207 II RCT registered in www.clinicaltrials.gov (NCT04856930).217 Avacopan is an oral C5a receptor antagonist under development for treatment of HS, LY 3041658 is a monoclonal antibody that neu- Antineutrophil cytoplasmatic antibodies-associ- tralizes chemokines that bind to the CXCR1 or ated vasculitis, and atypical hemolytic uremic CXCR2 receptors. It is being evaluated in a phase syndrome. A phase II RCT is currently ongoing II randomized placebo-controlled study for HS (NCT03852472),208 as well as a mechanistic (NCT04493502).218 study to examine the role of C5a receptors in HS (NCT04251663).209 LYS 006 is an orally administered leukotriene A4 (LTA4) hydrolase inhibitor under development JAK inhibitors. Tofacitinib is a Janus kinase inhib- for the treatment of HS and inflammatory acne. itor that has been used with successful results and Patients are being recruited in two phase II trials no safety concerns in two patients with Hurley III (NCT03827798 and NCT03497897).215,219 ulcerated HS resistant to other biologics.210 KT-474 is an oral small molecule that degrades the INCB054707 is an orally administered Janus IL-1 receptor-associated kinase 4 (IRAK4) and is kinase 1 (JAK1) inhibitor under development for currently being evaluated for the treatment of inter- the treatment of HS.199 Two recently completed leukin-1 receptor (IL-1R)/TLR-driven immune- phase II trials (NCT03569371, NCT03607487) inflammatory diseases. A first-in-human study have assessed the safety of this drug in 10 and 35 (phase I) evaluating safety, tolerability, drug phar- patients, respectively. In the NCT03607487 trial, macokinetics and pharmacodynamics is currently patients were randomized to receive placebo or in the recruitment phase (NCT04772885).220 INCB054707 30, 60, or 90 mg. Preliminary results indicate that 80% of patients treated with Several small molecules are currently being devel- 30 and 60 mg had grade 1–2 AEs. With the 90 mg oped by Pfizer, aiming for oral treatment of HS dose, 50% of patients had grade 1–2 AEs and a and other inflammatory diseases. Patient recruit- 37% had grade 3 AEs. 211,212 Another phase II ment is ongoing in a phase II, randomized, pla- RCT including 200 patients and intending to cebo-controlled 16-week study evaluating the assess drug efficacy is currently recruiting safety and efficacy of PF-06650833, (NCT04476043).213 PF-06826647, and PF-06700841 in the treat- ment of 192 adults with moderate-to-severe HS A phase II randomized placebo-controlled trial (NCT04092452).221 PF-06650833 is an IRAK4 with upadacitinib, another JAK inhibitor, is about inhibitor under development for the treatment of to start promptly (NCT04430855).214 HS and rheumatoid arthritis. PF-06826647 is a tyrosine kinase 2 (TYK2) inhibitor under devel- Other molecules under development. Iscalimab opment for the treatment of HS, psoriasis, and (CFZ533) is a fully human anti-CD40 IgG1 ulcerative colitis. PF-06700841 is a TYK2/JAK1 monoclonal antibody that blocks the CD40– inhibitor that prevents IL-12 and IL-23 signal- CD154 costimulatory pathway.199 A phase II ran- ing199 and is being developed for the treatment of domized, placebo-controlled trial assessing its HS and psoriasis.222 efficacy and safety in HS treatment is currently recruiting patients (NCT03827798).215 Where are we now and where are we going?. To date, ADA is the only approved biologic treat- Spesolimab, a monoclonal antibody directed ment with extensive evidence on HS. The exis- against the IL-36 receptor, which is under clinical tence of a subset of patients with failure to ADA development for pustular psoriasis and other has derived in an intensive search for other journals.sagepub.com/home/taj 21 Therapeutic Advances in Chronic Disease 12 molecules. The wide array of treatment options underlying pathogenetic heterogeneity of the dis- provides hope to those patients with advanced ease. Also, clinically distinguished phenotypes and treatment-refractory disease. have been shown to have different cytokine pro- files, and thus would probably correspond to As shown in this review, a large amount of new endotypes.5 Whether better responses can be molecules are being evaluated for HS treatment. achieved with a particular cytokine inhibitor in a As the pathogenesis of HS is becoming better concrete phenotype or endotype has not been known, it is logic to expect an increase in research studied so far.5 of new molecules.199,223 However, the identifica- tion of potential drugs for HS has been based on Furthermore, differences have been found preexistent drugs for other diseases (such as pso- between cytokine profiles in fistula drainage. riasis) rather than in translational research based Whether cytokines measured in pus secretion are on HS pathogenesis. This would explain poorer predictors of treatment response with specific results in RCTs compared with those in psoriasis; inhibitors is not known.55 even though common inflammatory pathways are activated, those in HS might be wider and A crucial point is to start treatment early, before different.19 the disease progresses to fibrotic or clinically irre- versible lesions. Efforts are being made to find Measurement of clinical outcomes in RCTs has disease biomarkers and to elucidate the factors of also been subject to some criticism. On one hand, poor prognosis and early disease progression. HiSCR counts the reduction in inflammatory This will help tailor treatment to HS patients.125,226 abscess and nodules, but it does not consider draining fistulas of advanced disease. On the In the authors’ opinion, we are heading to a preci- other hand, IHS4 considers nodules, abscesses, sion medicine approach with mediator-targeted and draining fistulas, and thus may be a more therapies that will provide the most suitable treat- representative outcome measure of HS. However, ment for HS depending on the predominant results in most RCTs are measured by HiSCR, inflammatory pathway alteration. We are far from which may lead to underestimation of response, this objective nowadays, but hopefully it will be since highly cicatricial disease can occur with low achieved in due course. inflammatory nodule counts.224 Extensive histori- cal use of HiSCR determines the need of evaluat- The main limitation of our review is potential bias ing future studies by HiSCR in order to obtain in the selection of information sources; the search comparable results, but a change (or supplemen- was extensive but not exhaustive, and not limited tation) of treatment outcome measures used in to randomized controlled trials. We did not clinical trials is highly advisable. intend to answer a specific research question with a meta-analysis, but to provide an expert review The cytokine cascade of HS appears complex and of the state of the art in HS treatment and the has been the main objective of research in recent existing lines of research. years, but the mechanisms underpinning the ini- tiation and progression of inflammation remain unknown. Although high serum and tissue levels Conclusion of some cytokines have been detected, their spe- HS is a complex multifactorial disease that cific blockade has not been leading to high rates requires combination therapy, including lifestyle of complete clinical response. This reaffirms the modifications, antimicrobial agents, hormonal implication of genetic and environmental factors therapy, surgery, and biologic therapy, if neces- and suggests the presence of unidentified agents sary. Due to the lack of effective treatments for modifying disease activity or determining drug moderate-to-severe HS, new therapeutic options resistance.19 are being studied, targeting specific cytokines involved in HS pathogenesis. Anti-IL-17 and anti- Our ignorance of the exact pathogenesis of HS is IL-1α inhibition seem to be promising therapeutic compounded by its highly heterogeneous charac- options for ADA-refractory moderate-to-severe ter, with different clinical presentations that have HS. Nevertheless, head-to-head clinical trials are led to define different phenotypes of the dis- not available yet. Current investigations on HS ease.225 These variants most likely represent the biomarkers will hopefully lead to improved 22 journals.sagepub.com/home/taj V Amat-Samaranch, E Agut-Busquet et al. disease assessment, and further knowledge of the References involved inflammatory phenomena and cytokine 1. Garg A, Lavian J, Lin G, et al. 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