The stepchild among inflammatory dermatoses

Correct interpretation of the symptoms of this heterogeneous inflammatory-intermittent disease is clinically significant. Diagnostic latency associated with mistreatment can contribute to serious complications and a high “burden of disease.” Therapy depends on the severity of the disease, and comorbidities should also be taken into account.

Hidradenitis suppurativa (HS), also called “acne inversa” or “maladie de Verneuil”, is a painful, inflammatory skin disease with a chronic intermittent course. Clinically, HS manifests as deep-seated inflammatory nodular lesions with abscesses and fistula formation in the apocrine gland-bearing areas of the body. Predilection sites include axillary, inguinal, and perianal regions [1]. Often the first manifestation occurs after puberty, the average age is between 21 and 23 years, females are more often affected than males [2,3]. In Europe, the 1-year prevalence in the general population is about 1%. The etiopathogenesis is not yet fully understood. Genetic, endocrine, microbiological, and immunological factors appear to play a role. A positive family history is present in 35-40%. Based on analyses of biopsies, HS is thought to be initiated due to occlusion of the terminal hair follicle in response to hyperkeratinization leading to nodule/cyst formation and eventual ruptured follicular epithelium [4–8]. This results in chronic inflammation with sinus and fistula formation and extensive dermal scarring.

Great influence on quality of life

If HS is not adequately treated, this relapsing disease can lead to serious complications. In addition to bacterial infections, fistula formation, and contractures, limitations in mobility and the development of squamous cell carcinoma are possible consequences [9]. Empirical data show that the quality of life, operationalized by the Dermatology Life Quality Index (DLQI), is significantly impaired in patients, whereby the extent of the burden varies depending on the severity of the symptoms: The mean DLQI was 5.77 for Hurley stage I, 13.1 for stage II, and 20.4 for stage III. These are high values considering that in moderate to severe psoriasis, the DLQI averages 12-13 [10,11]. Pain was perceived as most distressing by 85% of patients with HS, followed by swelling/inflammation and tenderness [12]. Impairment may result in inability to work, and foul odors and stains on clothing caused by purulent abscesses may lead to social stigma [13,14].

Diagnostic latency is a common phenomenon

In light of the substantial “burden of disease,” the fact that there is often a significant delay in diagnosis is very problematic. In a prospective study, the average diagnostic latency was 7.2 to 8.7 years for HS versus 1.6 to 4.8 years for psoriasis. In addition, patients with HS typically see many more physicians than psoriasis patients before the correct diagnosis is made [15]. Clinical examination is central in the diagnostic workup of HS. Skin biopsies are usually not required but may be useful to rule out a differential diagnosis with a gram-positive bacterial cause (e.g., boil or carbuncle). The diagnostic criteria are based on the following three main features of HS [16]: 1. Typical anatomical location: axillary, ingenuity and anogenital regions, 2. relapses and chronicle, 3. typical lesions: deep-seated nodules, comedones and/or fibrosis.
Depending on the clinical expression, 3 degrees of severity are distinguished according to Hurley [17]:

Stage I: Isolated, single or multiple painful abscesses, no scar strands;

Stage II: Recurrent painful abscesses with stranding and scarring, solitary or multiple, but not extensive;

Stage III: Diffuse, squamous, inflammatory, painful infiltrations, or multiple interconnected strands and abscesses. There is a risk of joint contractures as a result of pain-induced restriction of movement. Level I HS is the most common (65%), followed by Level II (31%) and Level III (4%) [17]. In addition to the Hurley classification scheme, the Sartorius score also exists [18,19]. In this scoring system, individual nodules and fistulas are counted, providing a dynamic measure of severe clinical disease.

HS patients are often overweight and smokers

The severity and course of HS correlate with body mass index (BMI), and according to several studies, an above-average number of HS patients are smokers (70-90%). Revuz et al. found an odds ratio (OR) of 4.42 for obese patients (BMI >30) and 12.55 for smoking compared with healthy controls [2]. Another study by Miller et al. found an OR of 6.38 for obesity [20]. Accordingly, there is also a high association between HS and diabetes mellitus (OR=5.74) and metabolic syndrome (OR=3.89) [20]. Overall, the prevalence of cardiovascular risk factors is significantly increased in individuals with HS compared with healthy individuals [21].

With respect to progression of HS, in a retrospective study of 846 individuals, the following five factors were associated with increased risk of progression from Hurley stage I to II or III: male sex, disease duration, BMI, years of smoking, and lesion location [22]. Other trigger factors of HS include mechanical irritation and certain comorbid conditions (e.g., polycystic ovary syndrome and depression) [23–26]. Some studies report increased comorbidity rates of HS and other inflammatory diseases. In addition to polycystic ovary syndrome, this also applies to inflammatory bowel disease and pyoderma gangraenosum [27–29].

Treatment concept adapted to the individual symptomatology

The Swiss Treatment Recommendations, published in 2017, were developed against the background of a lack of uniform guidelines until then and suggest the following therapeutic measures [34,35]:

Lifestyle factors: since smoking and obesity have the strongest correlation with disease severity, there is a general consensus that individuals with HS should be supported in smoking cessation and weight loss [2]. In addition, loose-fitting clothing is recommended to avoid mechanical stress.

Psychosocial support: HS has a strong negative impact on quality of life and can lead to depression and social integration problems, so psychosocial support measures should be considered.

Pharmacotherapy: The recommended treatment algorithm is based on the one hand on the severity according to Hurley (I-III) and on the other hand on disease-specific features (Fig. 1) . Topical disinfectants (e.g., triclosan, ammonium bituminosulfonate) or topical antibiotics (e.g., clindamycin solution) are recommended to prevent bacterial overinfection and reduce inflammation and maceration [30]. Inflamed nodules can be treated with intralesional steroids. When topical agents are not sufficient, systemic antibiotics are usually administered. Doxycycline (50-200 mg daily for 3-6 months) or rifampicin in combination with clindamycin (300 mg each twice daily for up to 3 months are suggested; zinc gluconate (3× 30 mg daily) may be added as a combination [31]. If antibiotics are insufficient or no longer effective, adalimumab should be considered according to Swissmedic’s dosage recommendation (160 mg in week 1, 80 mg in week 2, and 40 mg weekly thereafter) [32]. Alternatively, systemic acitretin can be used at a dosage of 0.2-0.5 mg/kg per day; in a recent study, this resulted in symptom reduction [33]. Many other agents can also be used in patients with diseases. These include dapsone (50-150 mg daily), metformin, systemic steroids, or cyclosporine A.

Surgical measures and laser excision: local excision of single lesions is recommended only in localized, well-circumscribed cases of Hurley I and II [1]. In all other cases, wide scalpel or_{CO2 laser excision of} the skin, including portions of the adipose tissue of the entire affected area, should be considered [1]. The exact surgical treatment plan, like conventional therapy, must also be clarified individually and in consultation with the patient. Physiotherapeutic measures are indicated until the wound is completely healed.

What role does the immune system play?

According to Jemec et al. continuous destruction of apocrine glands originating from terminal hair follicles is secondary to the inflammatory infiltrate (mainly neutrophils). These autoinflammatory processes result in increased production of proinflammatory cytokines such as interleukin-1β, TNF-α, interleukin-12, and interleukin-23 [14]. The European S1 guideline on HS mentions several empirical findings of characteristically altered immune responses [1]: In skin lesions of HS patients, a strong expression of the cytokines IL-1β, CXCL9 (MIG), IL-10, IL-11, BLC and IL-17A as well as a decrease in the expression of IL-20 and IL-22 was detected [36,37]. A 16-week s.c. therapy with the anti-TNF-α biologic adalimumab resulted in inhibition of cytokine expression, particularly IL-1β, CXCL9 (MIG), and BLC, and a decrease in the number of CD11c+ (dendritic cells), CD14+, and CD68+ cells in lesional skin [37]. The IL-23/Th17 signaling pathway is stimulated in hidradenitis suppurativa/acne inversa [7].

In a 2019 publication with first author Prof. Christoph Högenauer, MD, from the University of Graz (A), HS is classified as an immune-mediated inflammatory disease (IMID) [38]. According to the authors, this subsumes a clinically heterogeneous group of disorders that exhibit genetic, etiologic, and also clinical overlap. According to current evidence, common pathogenic mechanisms and cytokine-associated signal transduction pathways underlie IMID. The researchers state that individuals who have primary IMID are at increased risk for developing secondary IMID. HS is attributed to the former. This is a possible explanation for the comorbidity rates observed in HS of diseases that also have immune involvement.

Disproportionately common extradermal manifestations in HS patients include metabolic syndrome, spondyloarthropathies, and inflammatory bowel disease (IBD) [39–41]. According to data published in 2017 by Deckers et al. the prevalence of IBD in HS is 4 to 8 times higher than in the general population (0.8% ulcerative colitis; 2.5% Crohn’s disease) [42]. About half of all HS patients present with joint symptoms [43], including axial spondylarthritides [1,44]. As an implication for therapy management, an interdisciplinary exchange of information and, if necessary, a multidisciplinary treatment regimen are suggested.

Take-Home Messages

Hidradenitis suppurativa (HS) is a heterogeneous and highly variable inflammatory intermittent disease. The etiology is not yet fully understood; genetic, endocrine, microbiological, and immunological factors are thought to play a role.
Diagnostic classification is based on the Hurley scheme (I-III). A distinction is made between mild, moderate and severe forms of progression. Correct interpretation of symptoms is clinically significant, and diagnostic latency associated with mistreatment can contribute to serious complications and a high “burden of disease.”
Cardiovascular risk factors such as smoking and obesity are more prevalent than average in this patient population, as are metabolic syndrome, spondyloarthropathies, and IBD.
Treatment depends on the severity of the disease (Hurley I-III) and mainly includes topical therapy, systemic therapy, surgical measures and other methods (e.g. laser medical applications). Patients should be made aware of the harmful effects of smoking and obesity. In addition, psychosocial support can be helpful.

Literature:

Zouboulis CC, et al: S1 guideline for the treatment of hidradenitis suppurativa/acne inversa (number ICD-10 L73.2) (in German). J Dtsch Dermatol Ges 2012;10(suppl 5): S1-S31.
Revuz JE, et al: Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies. J Am Acad Dermatol 2008;59: 596-601.
Jemec GB, Heidenheim M, Nielsen NH: The prevalence of hidradenitis suppurativa and its potential precursor lesions. J Am Acad Dermatol 1996;35: 191-194.
Woodruff CM, Charlie AM, Leslie KS: Hidradenitis suppurativa: a guide for the practicing physician. Mayo Clin Proc 2015;90: 1679-1693.
Hunger RE, et al: Toll-like receptor 2 is highly expressed in lesions of acne inversa and colocalizes with C-type lectin receptor. Br J Dermatol 2008;158: 691-697.
Jemec GB, Hansen U: Histology of hidradenitis suppurativa. J Am Acad Dermatol 1996;34:994-999.
Schlapbach C, et al: Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa. J Am Acad Dermatol 2011;65: 790-798.
von Laffert M, et al: Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and at interfollicular epidermis. Exp Dermatol 2010;19: 533-537
Margesson LJ, Danby FW: Hidradenitis suppurativa. Best practice and research. Clin Obstet Gynaecol 2014;28: 1013-1027.
Alavi A: Hidradenitis suppurativa: demystifying a chronic and debilitating disease. J Am Acad Dermatol 2015;73(5 suppl 1): S1-S2.
Revicki D, et al: Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol 2008;158: 549-557.
Kimball A, et al: Patients’ experiences with hidradenitis suppurativa: a qualitative study of symptoms and impacts. J Am Acad Dermatol 2013; 68: AB57.
Kimball AB, et al: Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012;157: 846-855.
Jemec GB: Clinical practice. Hidradenitis suppurativa. New Engl J Med 2012;366: 158-164.
Saunte DM, et al: Diagnostic delay in hidradenitis suppurativa is a global problem. Br J Dermatol 2015;173: 1546-1549.
Zouboulis CC, et al: Hidradenitis suppurativa/acne inversa: criteria for diagnosis, severity assessment, classification and disease evaluation. Dermatology 2015;231: 184-190.
Revuz J: Hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2009;23: 985-998.
Sartorius K, et al: Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and obesity. Br J Dermatol 2009;161: 831-839.
Sartorius K, et al: Suggestions for uniform outcome variables when reporting treatment effects in hidradenitis suppurativa. Br J Dermatol 2003;149: 211-213.
Miller IM, et al: Association of metabolic syndrome and hidradenitis suppurativa. JAMA Dermatol 2014;150: 1273-1280.
Tzellos T, et al: Cardiovascular disease risk factors in patients with hidradenitis suppurativa: a systematic review and meta-analysis of observational studies. Br J Dermatol 2015;173: 1142-1155.
Schrader AM, et al: Hidradenitis suppurativa: a retrospective study of 846 Dutch patients to identify factors associated with disease severity. J Am Acad Dermatol 2014;71: 460-467.
Boer J, Nazary M, Riis PT: The role of mechanical stress in hidradenitis suppurativa. Dermatol Clin 2016;34: 37-43.
Nazary M, et al: Pathogenesis and pharmacotherapy of hidradenitis suppurativa. Eur J Pharmacol 2011;672: 1-8.
van der Zee HH, et al: The association between hidradenitis suppurativa and Crohn’s disease: in search of the missing pathogenic link. J Invest Dermatol 2016;136: 1747-1748.
Shavit E, et al: Psychiatric comorbidities in 3,207 patients with hidradenitis suppurativa. JEADV 2015;29: 371-376.
van der Zee HH, et al: Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010;162: 195-197.
Hsiao JL, et al: Hidradenitis suppurativa and concomitant pyoderma gangrenosum: a case series and literature review. Arch Dermatol 2010;146: 1265-1270.
Kraft JN, Searles GE: Hidradenitis suppurativa in 64 female patients: retrospective study comparing oral antibiotics and antiandrogen therapy. J Cutan Med Surg 2007;11:125-131.
Jemec GB, Wendelboe P: Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa. J Am Acad Dermatol 1998;39: 971-974.
Gener G, et al: Combination therapy with clindamycin and rifampicin for hidradenitis suppurativa: a series of 116 consecutive patients. Dermatology 2009;219: 148-154.
Kimball AB, et al: Two phase 3 trials of adalimumab for hidradenitis suppurativa. New Engl J Med 2016;375: 422-434.
Boer J, Nazary M: Long-term results of acitretin therapy for hidradenitis suppurativa. Is acne inversa also a misnomer? Br J Dermatol 2011; 164: 170-175.
Hunger R: “Let’s solve the HS (Acne Inversa) Challenge – Because Time is Ticking for the Patient. Inselspital Bern? Prof. Dr. med. Robert Hunger, SGDV Annual Congress, Basel, 19.09.2019
Hunger RE, et al: Swiss Practice Recommendations for the Management of Hidradenitis Suppurativa/Acne inversa. Dermatology, 2017, 233 (2-3), www.karger.com/Article/Fulltext/477459
van der Zee HH, et al: Adalimumab (anti-TNF-α) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study. Br J Dermatol 2012; 166: 298-305.
Wolk K, et al: Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa. J Immunol 2011, 186: 1228-1239.
Högenauer C, et al: Interdisciplinary management of immune-mediated diseases-an Austrian perspective. Journal of Gastroenterological and Hepatological Diseases 2019; 17: 108-124.
Fimmel S, Zouboulis CC: Comorbidities of hidradenitis suppurativa (acne inversa). Dermatoendocrinol 2010; 2(1): 9-16.
Sabat R, et al: Increased prevalence of metabolic syndrome in patients with acne inversa. PloS One 2012; 7(2):e31810.
Gold DA, et al: The prevalence of metabolic syndrome in patients with hidradenitis suppurativa. J Am Acad Dermatol 2014; 70(4): 699-703.
Deckers IE, et al: Inflammatory bowel disease is associated with hidradenitis suppurativa: results from a multicenter cross-sectional study. J Am Acad Dermatol 2017; 76(1): 49-53.
Shlyankevich J, et al: Hidradenitis suppurativa is a systemic disease with substantial comorbidity burden: a chart-verified case-control analysis. J Am Acad Dermatol 2014; 71(6):1144-1150.
Richette P, et al: Hidradenitis suppurativa associated with spondyloarthritis-results from a multicenter national prospective study. J Rheumatol 2014; 41(3): 490-494.