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Scala, E. Acne Inversa. Encyclopedia. Available online: https://encyclopedia.pub/entry/14739 (accessed on 28 March 2024).
Scala E. Acne Inversa. Encyclopedia. Available at: https://encyclopedia.pub/entry/14739. Accessed March 28, 2024.
Scala, Emanuele. "Acne Inversa" Encyclopedia, https://encyclopedia.pub/entry/14739 (accessed March 28, 2024).
Scala, E. (2021, September 29). Acne Inversa. In Encyclopedia. https://encyclopedia.pub/entry/14739
Scala, Emanuele. "Acne Inversa." Encyclopedia. Web. 29 September, 2021.
Acne Inversa
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Acne inversa, namely, Hidradenitis suppurativa (HS), is a chronic inflammatory skin disease affecting ~1% of the global population. HS typically occurs after puberty, with the average age of onset in the second or third decades of life and with a female predominance. Approximately one third of patients are genetically predisposed. Moreover, lifestyle factors, such as smoking and obesity, play a crucial role in the clinical course of HS.

hidradenitis suppurativa diagnosis pathogenesis treatments translational studies

1. Introduction

Due to its chronic nature and frequently occurring relapses, HS has a great impact on the patients’ quality of life, deeply affecting social, working, and psychological aspects [1][2][3][4]. Therefore, early diagnosis is very important for HS patients in order to ensure the best possible course of this stigmatizing and painful disease.

1.1. Clinical Aspects

HS is usually localized in the apocrine gland-bearing areas ( Figure 1 ). According to the modified Dessau definition, three diagnostic criteria should be matched: presence of typical lesions, typical locations, and chronicity [5]. Deep-seated painful nodules, abscesses, suppurative sinus tracts or tunnels, bridged scars, and double- and multi-ended comedones (also known as “tombstone comedones”) are described as typical lesions. Commonly, patients experience pain, malodor, a burning sensation, and an itch [6]. Chronicity, defined as two recurrences within the period of six months, is based on a complex pathogenesis underlying the disease; nodules and abscesses can rupture, bleed, and produce purulent discharge. The role of bacteria, infections, and superinfections in HS is still debated and controversial, but they probably have a role in promoting the chronicity of HS [7]. The persistence of the pathology entails the occurrence of dermal contracture and fibrosis of lesional skin. Intertriginous anatomic locations are typically involved, particularly the axillary, infra- and intermammary, inguinal, perineal, perianal, and gluteal regions [8].

HS may less frequently occur in the lower abdomen, suprapubic, retroauricular, nape, eyelids, and scalp [9][10]. Since diagnosis of HS may typically be delayed for years, in order to enhance a correct diagnosis, other factors should be investigated; above all, a family history of HS and history of other follicular occlusion diseases [11]. Moreover, the identification of pathogenic microbes should be evaluated and it could be useful in the therapeutic management, even if a primary infection is not the principal cause of HS [12]. Considering the lack of knowledge to date on the exact pathogenetic mechanism underlying the onset of HS, the phenotypic variants available today still receive criticisms and proposals for change. Three clinical subtypes of HS have been described: axillary-mammary, follicular, and gluteal [13]. According to another classification by van der Zee et al. [14], there are six phenotypes of HS: (i) regular type; (ii) frictional furuncle type; (iii) scarring folliculitis type; (iv) conglobata type; (v) syndromic type; and (vi) ectopic type. Recently, it was suggested to distinguish between a follicular subtype and an inflammatory phenotype, which is usually associated with a worse course of HS [15].

Figure 1. Clinical images of typical HS lesions in groin (A), and axilla (B,C). Superficial papules, small abscesses without scarring or sinus tracts, Hurley stage I (A). Multiple, recurrent abscesses with initial sinus tracts and cicatrization, Hurley stage II (B). Diffuse involvement of the axillary region with large abscesses, interconnected tracts, and scarring, Hurley stage III (C).

1.2. Severity Assessment

The first severity classification of HS was proposed by Hurley in 1989, categorizing patients into three stages based mainly on the presence of sinus tracts and scarring. The Hurley scoring system is a simple tool, nevertheless it is non-quantitative and static. Indeed, the use of this method in clinical studies may have significant limitations [16]. A more complex and detailed severity scoring method, called the Sartorius Scoring system, better suited to assess disease severity and grade of inflammation, was later proposed. Even though it is more accurate and precise in defining the severity of the disease, the Sartorius score may be time-consuming in routine clinical practice. Still today, the Hurley staging and the Sartorius scoring, together with HS Physician Global Assessment systems are the most commonly used assessment tools [17][18]. In addition, the HS Clinical Response (HiSCR), defined as the reduction in at least 50% of total abscess and inflammatory nodule count, with no increase in abscess count and no increase in draining fistula count relative to baseline, is used mainly to assess treatment effects in trials [19]. Recently, several other clinical measures for assessing HS disease severity were described, including the recently proposed HS Severity Score System (IHS4), the Acne Inversa Severity Index, and the Severity Assessment of HS score, which need further validation [20][21][22]. Ultrasound (US) aids in the diagnosis and assessment of HS disease severity [23]. Different subclinical lesions have been identified and categorized using US, and their recognition is able to modify a therapeutic approach [24]. Wortsman and colleagues proposed a sonographic scoring system for HS (SOS-HS) that combined the results of parameters included in Hurley’s classification with the relevant sonographic findings [23]. Finally, it is well known how HS may have a significant impairment of patients’ quality of life (QoL). Therefore, specific QoL tools have been developed and validated for HS: HiSQOL [25], HSQoL-24 [26], and patient-reported outcome (PRO) questionnaires [27]. Recently, a new graphical tool able to better describe HS burden, the so-called HIDRAdisk, has been introduced [28][29].

2. Future Treatments and Personalized Therapies

Advances in understanding HS pathogenesis are leading to the future expansion of the disease treatment armamentarium [30]. Indeed, several small molecules and biologics are under investigation, for moderate-to-severe HS therapy (Table 1). With phase III trials ongoing, the anti-IL-17 agents bimekizumab (which blocks IL-17 A and F) and secukinumab (which blocks IL17A) are in the most advanced stage of clinical development showing promising results, based on the extensive evidence of the activation and upregulation of the IL-17 pathway in HS inflammation [31]. Even if controversial data regarding possible paradoxical reactions have been described [32], recent studies have showed only partially confirmed effectiveness of secukinumab in the treatment of moderate-severe HS, since HiSCR was achieved only by 41% of patients at week 28 [33]. Bermekimab, which targets IL-1α, has shown resolution of inflammatory lesions and pain in a phase II trials on moderate-to-severe HS while phase II trials are also being conducted for spesolimab which acts on neutrophil recruitment and activation by targeting IL-36 [31].
In addition, modulation of several proinflammatory cytokines and chemokines, such as TNF-α, IL-12/IL-23, CXCL9, and CXCL10, through administration of the oral phosphodiesterase-4 inhibitor apremilast was positively tested in mild to moderate HS in a phase II study [34]. However, drugs which are being tested for HS are very numerous and further include also complement 5a (C5a) and C5a receptor blocking agents (avacopan and IFX-1), janus kinase (JAK), signalling inhibitors (tofacitnib and upadacitinib), anti-CD40 (iscalimab), and anti-iIL23 agents (guselkumab and risankizumab) [31][35]. Furthermore, case reports or case series also show good results for other drugs, such as certolizumab pegol (anti-TNF-α) [36][37][38], tildrakizumab (anti-IL23) [39], ixekizumab (anti-IL17) [40], and brodalumab (anti-IL17 receptor) [41]. In this crowded future treatment scenario, it should be emphasized that HS is a complicated disease that involves both pathological and environmental factors. Hence, treating HS will continue to involve a multidisciplinary approach with monotherapy, often tending not to be efficacious or enough alone. Future treatment should be guided by personalized therapy, biomarkers, and pharmacogenomics (precision medicine), which should drive the therapeutic choice in order to maximize clinical outcomes and limit adverse events following patients peculiarities at genetic and phenotypic level [42].
Table 1. Ongoing and upcoming interventional trials on HS.
Intervention/Compound Target Type Phase Number of Studies ClinicalTrials.gov Identifier
Avacopan C5a receptor Systemic drug 2 1 NCT03852472
Bimekizumab IL-17A, IL-17F Systemic drug 3 2 NCT04242446, NCT04242498
Iscalimab (CFZ533), LYS006 CD40,
LTA4H (respectively)
Systemic drug 2 1 NCT03827798
CSL324 G-CSF receptor Systemic drug 1 1 NCT03972280
Imsidolimab IL-36 receptor Systemic drug 2 1 NCT04856930
INCB05470 JAK-1 Systemic drug 2 1 NCT04476043
KT-474 IRAK4 Systemic drug 1 1 NCT04772885
LY3041658 ELR + CXC chemokines Systemic drug 2 1 NCT04493502
Metformin unknown (anti-inflammatory) Systemic drug 3 1 NCT04649502
PF-06650833,
PF-06700841,
PF-06826647
IRAK4, TYK2+JAK1,
TYK2 (respectively)
Systemic drug 2 1 NCT04092452
Risankizumab IL-23p19 Systemic drug 2 1 NCT03926169
Secukinumab IL-17A Systemic drug 3 3 NCT04179175, NCT03713619, NCT03713632
Spesolimab IL-36 receptor Systemic drug 2 2 NCT04876391, NCT04762277
Tofacitinib pan-JAK Systemic drug 2 1 NCT04246372
Upadacitinib JAK-1 Systemic drug 2 1 NCT04430855
Local therapy (wound dressings, creams, gels, sclerotherapy, AMP, triamcinolone)   Local therapy all 9 NCT04648631, NCT04194541, NCT04388163, NCT04354012, NCT04541550, NCT02805595, NCT04582669, NCT04756336, NCT04414514
Laser treatment   Laser n.a. 2 NCT04508374, NCT03054155
Surgery (different procedures +/−ADA or NPWT+/−i)   Surgery n.a. 4 NCT04526561, NCT04325607, NCT03784313, NCT03221621
Other (acupuncture, HS management, electronic reporting)   Other n.a./4 3 NCT04218422, NCT04200690, NCT04132388
ADA, adalimumab; AMP, Allogeneic Micronized Amniotic Membrane Product; CD, cluster of differentiation; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; IRAK4, interleukin-1 receptor associated kinase 4; JAK, janus kinase; LTA4H, leukotriene A4 hydrolase; n.a., not applicable; NPWT+/−i, negative pressure wound therapy with(+)/without(−) instillation; TNF, tumor necrosis factor.

3. Conclusions

HS is a chronic inflammatory skin disorder with many contributing factors. It can greatly impact patients’ quality of life and social and work activities due to frequent disease relapses with painful and foul-smelling lesions. Therefore, prompt treatment is necessary to reduce the HS burden. Available medicaments are limited, mostly off-label, and surgical interventions are often required to achieve remission. Immunomodulatory therapies targeting specific cytokines might represent an effective option in controlling this condition. Adalimumab, a TNF-α blocker, is the only FDA-approved biological drug for moderate-to-severe HS, whereas the majority of cytokines’ selective inhibitors (e.g., IL-12/23 and IL-17) are still in their early phases. However, clinical efficacy of all novel treatments reported so far is modest. Thus, HS remains a challenging disease to treat, and patients often need a multidisciplinary approach. Future translational studies are needed to better define this enigmatic skin disorder.

References

  1. Napolitano, M.; Megna, M.; Timoshchuk, E.A.; Patruno, C.; Balato, N.; Fabbrocini, G.; Monfrecola, G. Hidradenitis suppurativa: From pathogenesis to diagnosis and treatment. Clin. Cosmet. Investig. Dermatol. 2017, 10, 105–115.
  2. Chernyshov, P.V.; Finlay, A.Y.; Tomas-Aragones, L.; Poot, F.; Sampogna, F.; Marron, S.E.; Zemskov, S.V.; Abeni, D.; Tzellos, T.; Szepietowski, J.C.; et al. Quality of Life in Hidradenitis Suppurativa: An Update. Int. J. Environ. Res. Public Health 2021, 18, 6131.
  3. Weigelt, M.A.; Milrad, S.F.; Kirby, J.R.S.; Lev-Tov, H. Psychosocial impact of hidradenitis suppurativa: A practical guide for clinicians. J. Dermatol. Treat. 2021, 14, 1–23.
  4. Montero-Vilchez, T.; Diaz-Calvillo, P.; Rodriguez-Pozo, J.A.; Cuenca-Barrales, C.; Martinez-Lopez, A.; Arias-Santiago, S.; Molina-Leyva, A. The Burden of Hidradenitis Suppurativa Signs and Symptoms in Quality of Life: Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health 2021, 18, 6709.
  5. Revuz, J. Hidradenitis suppurativa. J. Eur. Acad. Dermatol. Venereol. 2009, 23, 985–998.
  6. Lipsker, D.; Severac, F.; Freysz, M.; Sauleau, E.; Boer, J.; Emtestam, L.; Matusiak, Ł.; Prens, E.; Velter, C.; Lenormand, C.; et al. The ABC of Hidradenitis Suppurativa: A Validated Glossary on how to Name Lesions. Dermatology 2016, 232, 137–142.
  7. Marasca, C.; Tranchini, P.; Marino, V.; Annunziata, M.C.; Napolitano, M.; Fattore, D.; Fabbrocini, G. The pharmacology of antibiotic therapy in hidradenitis suppurativa. Expert Rev. Clin. Pharmacol. 2020, 13, 521–530.
  8. Revuz, J.E.; Jemec, G.B.E. Diagnosing Hidradenitis Suppurativa. Dermatol. Clin. 2016, 34, 1–5.
  9. Agut-Busquet, E.; Romaní, J.; Ribera, M.; Luelmo, J. Hidradenitis suppurativa of the nape: Description of an atypical phenotype related to severe early-onset disease in men. J. Dermatol. 2019, 46, 149–153.
  10. Esmann, S.; Dufour, D.N.; Jemec, G.B. Questionnaire-based diagnosis of hidradenitis suppurativa: Specificity, sensitivity and positive predictive value of specific diagnostic questions. Br. J. Dermatol. 2010, 163, 102–106.
  11. Bettoli, V.; Pasquinucci, S.; Caracciolo, S.; Piccolo, D.; Cazzaniga, S.; Fantini, F.; Binello, L.; Pintori, G.; Naldi, L. The Hidradenitis suppurativa patient journey in Italy: Current status, unmet needs and opportunities. J. Eur. Acad. Dermatol. Venereol. 2016, 30, 1965–1970.
  12. Bettoli, V.; Manfredini, M.; Massoli, L.; Carillo, C.; Barozzi, A.; Amendolagine, G.; Ruina, G.; Musmeci, D.; Libanore, M.; Curtolo, A.; et al. Rates of antibiotic resistance/sensitivity in bacterial cultures of hidradenitis suppurativa patients. J. Eur. Acad. Dermatol. Venereol. 2019, 33, 930–936.
  13. Canoui-Poitrine, F.; Le Thuaut, A.; Revuz, J.E.; Viallette, C.; Gabison, G.; Poli, F.; Pouget, F.; Wolkenstein, P.; Bastuji-Garin, S. Identification of three hidradenitis suppurativa phenotypes: Latent class analysis of a cross-sectional study. J. Investig. Dermatol. 2013, 133, 1506–1511.
  14. van der Zee, H.H.; Jemec, G.B. New insights into the diagnosis of hidradenitis suppurativa: Clinical presentations and phenotypes. J. Am. Acad. Dermatol. 2015, 73, S23–S26.
  15. Martorell, A.; Jfri, A.; Koster, S.B.L.; Gomez-Palencia, P.; Solera, M.; Alfaro-Rubio, A.; Hueso, L.; Sanz-Motilva, V. Defining hidradenitis suppurativa phenotypes based on the elementary lesion pattern: Results of a prospective study. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 1309–1318.
  16. Thorlacius, L. Severity staging of hidradenitis suppurativa: Is Hurley classification the answer? Br. J. Dermatol. 2019, 181, 243–244.
  17. Sartorius, K.; Emtestam, L.; Jemec, G.B.E.; Lapins, J. Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and obesity. Br. J. Dermatol. 2009, 161, 831–839.
  18. Sartorius, K.; Killasli, H.; Heilborn, J.; Jemec, G.B.E.; Lapins, J.; Emtestam, L. Interobserver variability of clinical scores in hidradenitis suppurativa is low: Hidradenitis suppurativa scoring variability. Br. J. Dermatol. 2010, 162, 1261–1268.
  19. Kimball, A.B.; Sobell, J.M.; Zouboulis, C.C.; Gu, Y.; Williams, D.A.; Sundaram, M.; Teixeira, H.D.; Jemec, G.B. 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. J. Eur. Acad. Dermatol. Venereol. 2016, 30, 989–994.
  20. Chiricozzi, A.; Faleri, S.; Franceschini, C.; Caro, R.D.; Chimenti, S.; Bianchi, L. AISI: A New Disease Severity Assessment Tool for Hidradenitis Suppurativa. Wounds 2015, 27, 258–264.
  21. Zouboulis, C.C.; Tzellos, T.; Kyrgidis, A.; Jemec, G.B.E.; Bechara, F.G.; Giamarellos-Bourboulis, E.J.; Ingram, J.R.; Kanni, T.; Karagiannidis, I.; Martorell, A.; et al. Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity. Br. J. Dermatol. 2017, 177, 1401–1409.
  22. Hessam, S.; Scholl, L.; Sand, M.; Schmitz, L.; Reitenbach, S.; Bechara, F.G. A Novel Severity Assessment Scoring System for Hidradenitis Suppurativa. JAMA Dermatol. 2018, 154, 330–335.
  23. Wortsman, X.; Moreno, C.; Soto, R.; Arellano, J.; Pezo, C.; Wortsman, J. Ultrasound in-depth characterization and staging of hidradenitis suppurativa. Dermatol. Surg. 2013, 39, 1835–1842.
  24. Marasca, C.; Marasca, D.; Megna, M.; Annunziata, M.C.; Fabbrocini, G. Ultrasound: An indispensable tool to evaluate the outcome of surgical approaches in patients affected by hidradenitis suppurativa. J. Eur. Acad. Dermatol. Venereol. 2020, 34, e413–e414.
  25. Kirby, J.; Thorlacius, L.; Villumsen, B.; Ingram, J.; Garg, A.; Christensen, K.; Butt, M.; Esmann, S.; Tan, J.; Jemec, G. The Hidradenitis Suppurativa Quality of Life (HiSQOL) score: Development and validation of a measure for clinical trials. Br. J. Dermatol. 2019, 183, 340–348.
  26. Marrón, S.; Gómez-Barrera, M.; Aragonés, L.T.; Díaz, R.D.; Rull, E.V.; Álvarez, M.M.; Puig, L. Development and Preliminary Validation of the HSQoL-24 Tool to Assess Quality of Life in Patients with Hidradenitis Suppurativa. Actas Dermo-Sifiliogr. 2019, 110, 554–560.
  27. Kimball, A.B.; Sundaram, M.; Banderas, B.; Foley, C.; Shields, A.L. Development and initial psychometric evaluation of patient-reported outcome questionnaires to evaluate the symptoms and impact of hidradenitis suppurativa. J. Dermatol. Treat. 2018, 29, 152–164.
  28. Chiricozzi, A.; Bettoli, V.; De Pità, O.; Dini, V.; Fabbrocini, G.; Monfrecola, G.; Musumeci, M.; Parodi, A.; Sampogna, F.; Pennella, A.; et al. HIDRAdisk: An innovative visual tool to assess the burden of hidradenitis suppurativa. J. Eur. Acad. Dermatol. Venereol. 2018, 33, e24–e26.
  29. Fabbrocini, G.; Marasca, C.; Megna, M.; Peris, K.; HS Quality of Life Study Group. Age and gender influence on HIDRAdisk outcomes in adalimumab-treated hidradenitis suppurativa patients. J. Eur. Acad. Dermatol. Venereol. 2019, 33, 25–27.
  30. van Straalen, K.R.; Schneider-Burrus, S.; Prens, E.P. Current and future treatment of hidradenitis suppurativa. Br. J. Dermatol. 2020, 183, e178–e187.
  31. Zouboulis, C.C.; Frew, J.W.; Giamarellos-Bourboulis, E.J.; Jemec, G.B.E.; Del Marmol, V.; Marzano, A.V.; Nikolakis, G.; Sayed, C.J.; Tzellos, T.; Wolk, K.; et al. Target molecules for future hidradenitis suppurativa treatment. Exp. Dermatol. 2021, 30, 8–17.
  32. Marasca, C.; Megna, M.; Balato, A.; Balato, N.; Napolitano, M.; Fabbrocini, G. Secukinumab and hidradenitis suppurativa: Friends or foes? JAAD Case Rep. 2019, 5, 184–187.
  33. Ribero, S.; Ramondetta, A.; Fabbrocini, G.; Bettoli, V.; Potenza, C.; Chiricozzi, A.; Licciardello, M.; Marzano, A.V.; Bianchi, L.; Rozzo, G.; et al. Effectiveness of Secukinumab in the treatment of moderate-severe hidradenitis suppurativa: Results from an Italian multicentric retrospective study in a real-life setting. J. Eur. Acad. Dermatol. Venereol. 2021, 35, e441–e442.
  34. Kerdel, F.R.; Azevedo, F.A.; Kerdel Don, C.; Don, F.A.; Fabbrocini, G.; Kerdel, F.A. Apremilast for the Treatment of Mild-to-Moderate Hidradenitis Suppurativa in a Prospective, Open-Label, Phase 2 Study. J. Drugs Dermatol. 2019, 18, 170–176.
  35. Folkes, A.S.; Hawatmeh, F.Z.; Wong, A.; Kerdel, F.A. Emerging drugs for the treatment of hidradenitis suppurativa. Expert Opin. Emerg. Drugs 2020, 25, 201–211.
  36. Holm, J.G.; Jørgensen, A.R.; Yao, Y.; Thomsen, S.F. Certolizumab pegol for hidradenitis suppurativa: Case report and literature review. Dermatol. Ther. 2020, 2, e14494.
  37. Wohlmuth-Wieser, I.; Alhusayen, R. Treatment of hidradenitis suppurativa with certolizumab pegol during pregnancy. Int. J. Dermatol. 2020, 60, e140–e141.
  38. Esme, P.; Akoglu, G.; Caliskan, E. Rapid Response to Certolizumab Pegol in Hidradenitis Suppurativa: A Case Report. Skin Appendage Disord. 2021, 7, 58–61.
  39. Kok, Y.; Nicolopoulos, J.; Dolianitis, C. Tildrakizumab as a potential long-term therapeutic agent for severe Hidradenitis Suppurativa: A 15 months experience of an Australian institution. Australas. J. Dermatol. 2021, 62, e313–e316.
  40. Megna, M.; Ruggiero, A.; Di Guida, A.; Patrì, A.; Fabbrocini, G.; Marasca, C. Ixekizumab: An efficacious treatment for both psoriasis and hidradenitis suppurativa. Dermatol. Ther. 2020, 33, e13756.
  41. Yoshida, Y.; Oyama, N.; Iino, S.; Shimizu, C.; Hasegawa, M. Long-standing refractory hidradenitis suppurativa responded to a brodalumab monotherapy in a patient with psoriasis: A possible involvement of Th17 across the spectrum of both diseases. J. Dermatol. 2021, 48, 916–920.
  42. Tricarico, P.M.; Boniotto, M.; Genovese, G.; Zouboulis, C.C.; Marzano, A.V.; Crovella, S. An Integrated Approach to Unravel Hidradenitis Suppurativa Etiopathogenesis. Front. Immunol. 2019, 10, 892.
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