HS Overview

What is the global prevalence of HS?

In recent years, a range of studies have estimated the global prevalence of HS as being between 0.00033–4.1%, and more recent studies in the United States and Europe have potentially narrowed this range to 0.7–1.2%^2–15.

However, in a systematic review and meta-analysis (N=118,760,093) of HS cases, differences in prevalence were found when stratifying by geographic region (Figure 1)¹⁶. The highest prevalence was seen in Europe, 0.8% (0.5–1.3%), followed by the USA, 0.2% (0.1–0.4%), Asia-Pacific, 0.2% (0.01–2.2%), and South America, 0.2% (0.01–0.9%)¹⁶.

Figure 1. Forest plot of pooled hidradenitis suppurativa prevalence, stratified by geographic region (Adapted¹⁶).

One study included in the systematic review and meta-analysis was a population-based observational and case–control study of hospital episode statistics from the UK Clinical Practice Research Datalink (CPRD) by Ingram et al.⁵.

In this study, it was found that around 30% of people with HS were previously unrecognised and 18,417 cases had a history of 1–4 flexural skin boils, potentially giving rise to a higher prevalence of 1.19%⁵.

HS is often underdiagnosed and has a worldwide mean diagnostic delay of approximately 7–10 years^17,18

Does HS prevalence differ by demographic?

HS appears to exhibit similar clinical features and endocrine comorbidities in both paediatric patients and adults^19,20. However, HS is most highly prevalent between the third and fourth decades of life^{2–4,21–23}. Moreover, HS appears to be very rare in women before menarche, although paediatric cases have been described²⁴.

In the study by Ingram et al. ⁵, it was noted that the peak HS prevalence of 15.1 per 1,000 occurred in the fifth decade of life (Figure 2). The mean female-to-male ratio was 2.9:1 across the age groups⁵.

Figure 2. Prevalence of physician-diagnosed hidradenitis suppurativa cases by gender (Adapted⁵).

However, while studies have shown an increased prevalence of HS in women in European and North American populations^6,7,21,22, studies in Asia have predominantly described cases of HS in men^2,5,25–27.

In addition to gender, the Calao et al. study found statistically significant differences in age (P<0.0001), body mass index (P=0.0307), smoking status (P<0.0001), employment status (P<0.0001) and income (P=0.0321)².

Race-specific differences in prevalence are difficult to define because of the limited reporting of ethnicity in HS studies²⁸. However, African Americans are more likely to have clinic visits for HS than White Americans in the United States (OR, 2.00; P=0.047)²⁹ and may be more affected by HS overall^29–33.

What are the symptoms of HS?

People with HS develop painful and inflamed nodules, abscesses and pus-discharging tunnels (known as sinus tracts and fistulas) between skin folds of the armpits, groin, gluteal and perianal areas of the body (Figure 3)³⁵.

Figure 3. Common skin on skin locations in which hidradenitis suppurativa can develop (Adapted³⁶).

The most impactful symptom reported by most people with HS is chronic pain, which ranges from mild to severe in intensity^18,37. Usually resulting from the inflammatory nodules or abscesses associated with the disease, pain is reported by 97% of patients during their disease course³⁷. HS causes both nociceptive pain (resulting from tissue injury and inflammation) and neuropathic pain (likely arising from chronic inflammation and somatosensory nervous system dysfunction)³⁸. Acute pain is predominantly nociceptive, while chronic pain can be categorised as nociceptive or neuropathic³⁸.

The pain associated with HS may be of a higher intensity than other dermatological conditions^39–41Patients describe the pain as hot, burning, pressing, stretching, cutting, sharp, taut, splitting, gnawing, sore, throbbing or aching^37,39.

The physical manifestations of HS, including severe pain and purulent secretions that restrict movement and produce an unpleasant smell, have a profound impact on the lives of patients⁴².

Pruritus is also a frequently mentioned symptom⁴², which has been shown in two previous studies to have a prevalence of 41.2–67.6%^37,43. Although no specific correlation was found between pruritus intensity and disease severity, the intensity of the pruritus was associated with a negative impact on quality of life^37,43.

How do the symptoms of HS progress?

When HS begins to develop, it usually progresses through the following stages³⁶:

• Area of skin feels uncomfortable
• Tender, deep nodules appear
• Nodules grow and start to join together
• Large, painful, abscesses break open
• Blackhead-like spots appear
• Abscesses heal slowly (if at all) and return; tunnels (or sinus tracts) and scars form

Comparatively little is known about the long-term evolution of HS. Some studies using self-reported real-world data have shown that approximately one-third of patients achieve remission, while one-third remain unchanged or worsen⁴⁴. One-third achieve amelioration, possibly because of improved coping over time⁴⁴.

What are the comorbidities of HS?

Outside of the physical burden of HS, a broad range of comorbidities have been observed in patients, including^45,46,47:

• Acne
• Dissecting cellulitis of the scalp
• Down syndrome
• Inflammatory bowel disease
• Lymphomas
• Cardiovascular disease (including hypertension and major adverse cardiac events)
• Metabolic disease (including obesity, dyslipidaemia, diabetes mellitus and metabolic syndrome)
• Sleep disorders
• Pilonidal disease
• Polycystic ovarian syndrome
• Mood disorders (including depression, anxiety and suicidality)
• Pyoderma gangrenosum
• Sexual dysfunction
• Spondyloarthritis
• Substance use disorder (including alcohol, tobacco, and opioids)

Most notably, a study of 5,964 people with HS found an association with substantially increased mortality (incidence rate ratio [IRR], 1.35; 95% CI, 1.15–1.59), especially due to cardiovascular events (IRR, 1.95; 95% CI, 1.42–2.67)⁴⁸.

How does hidradenitis suppurativa impact quality of life?

According to studies of quality-of-life impairment, people with HS have greatly reduced physical and mental health (Figure 4)^40,51.

Figure 4. Impact of hidradenitis suppurativa on patient quality of life as measured by the Short Form 36 items survey, with scores representing the percentage of the total possible score achieved (Adapted⁴²).

Using Short Form 36 items survey (SF-36) general health questionnaire scores, these studies have found that the domains with notably lower scores were role physical, bodily pain, general health, perception, social functioning and role emotional, compared with the general population^40,51.

Patients have reported negative impacts on their sex life52 as well as their professional lives, which can negatively affect their economic situation^53,54In more severe disease (Hurley stage 3), physical functioning, vitality, and mental health were also found to be significantly deteriorated⁵¹.

What is the psychological burden of HS?

People with dermatoses are generally considered to be at higher risk of psychiatric disorders than the overall population^55,56. However, people with HS are thought to be particularly at risk given the impact on quality of life caused by their symptoms and associated comorbidities⁵⁵.

A Finnish nationwide registry study (N=4,381) aimed to clarify the association between HS and its psychiatric comorbidities. In the study, people with HS were compared with those with psoriasis, given their elevated risk of psychological comorbidities and melanocytic naevi⁵⁵.

It was found that the total prevalence of psychotic disorders was 4.7% in the HS group, compared with 3.3% in the psoriasis group (OR, 1.46; 95% CI; 1.24–1.72), and 1.7% in the melanocytic naevi group (OR, 2.74; 95% CI, 2.29–3.28)⁵⁵.

Notably, gender differences were observed (Figure 5), with mental disorders being more frequently observed in females (OR, 1.28; 95% CI, 1.15–1.41) than males (OR, 1.46; 95% CI, 1.28–1.66) with HS (25.5% and 22.0%, respectively).

Figure 5. Gender differences in the odds ratios for psychiatric disorders in people with hidradenitis suppurativa (Adapted⁵⁵).

Major depressive disorder was found to be the most common psychiatric comorbidity across all groups, but was shown to occur more frequently in people with HS than in those with psoriasis (15.3% vs 12.1%; OR, 1.31; 95% CI, 1.19–1.44) or melanocytic naevi (8.3%; OR, 2.00; 95% CI, 1.81–2.22)⁵⁵.

Similar results were observed in a Danish registry study (N=7,732), showing a significant association between HS and depression (OR, 1.9), anxiety (OR, 2.34), and hospitalisations and usage of antidepressants or anxiolytics (OR, 2.02–2.65)⁴⁹. The study found that the prevalence of depression (1.6%) and anxiety (0.8%) were higher than in the background population⁴⁹.

The increased risk of depression associated with HS may even go beyond the burdens associated with the disease itself. It has been suggested that the overexpression of inflammatory markers in HS may play a role in the development of depression^57–60.

Does HS cause loneliness, stigmatisation, and an increased risk of suicide?

People with HS have significantly lower levels of self-esteem as well as higher levels of loneliness and social isolation⁵⁰.

Moreover, the emotional impact of HS increases the feeling of needing to isolate, due to the fear of stigmatisation⁵². However, while these feelings of stigmatisation and loneliness are seen to be linked to the clinical severity of HS, the reduction of self-esteem has instead been shown to be linked to the location of the lesions^50,61.

As shown in the Danish registry study (N=7,732), HS has a profound impact on the risk of suicide (HR, 2.42), even following adjustment for age, sex, socioeconomic status, smoking, alcohol misuse and healthcare consumption⁴⁹.

Despite this burden, the number of therapies approved for HS is limited, resulting in an enormous unmet medical need⁶². An increased understanding of the pathophysiology of HS is therefore essential, as it may open up new treatment possibilities.

What are the causes and risk factors of HS?

Dr Joslyn Kirby describes the factors that can influence the risk of developing HS, including genetics and lifestyle.

While the pathophysiology of HS is complex, it is strongly influenced by lifestyle factors such as smoking and obesity; physical triggers such as friction and increased temperature; and changes in the skin microbiome⁶³.

HS is also suspected to have a genetic predisposition, with studies showing heritability of up to 80%^63,64. However, no causative genes have yet been conclusively identified. On the basis of current genetic knowledge, the disease can be categorised as familial, sporadic, syndromic or ‘HS plus’, which occurs in association with other conditions such as Dowling–Degos disease and familial Mediterranean fever⁶⁴. There is a high level of heterogeneity between these forms of HS; however, there may be an autosomal dominant mode of inheritance of familial HS⁶⁵.

Research is ongoing to further elucidate the genetics related to HS. Genome-wide association studies and advanced molecular genetic techniques may reveal causative genes and loci, which may enable personalised management approaches^63,65.

How does HS develop?

Beginning at the hair follicle, the earliest histologically detectable events in HS include³⁴:

• Perivascular and perifollicular immune cell infiltration
• Hyperkeratosis
• Hyperplasia of the infundibular epithelium (infundibular acanthosis)

These alterations of the infundibular epithelium induce follicular occlusion, or ‘plugging’, followed by a stasis of follicular content, anaerobic bacterial proliferation, and hair follicle dilatation (Figure 6)³⁴.

As follicular cells become damaged, bacterial components and danger-associated molecular patterns (DAMPs) are released, which may further stimulate inflammatory responses. It has been suggested that local macrophages may become activated, leading to the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β and tumour necrosis factor (TNF) (Figure 6)³⁴.

Figure 6. Initial events involved in the pathogenesis of hidradenitis suppurativa (Adapted³⁴). AP-1, activator protein 1; CCL, chemokine (C-C motif) ligand; CXCL, chemokine (C-X-C motif) ligand; IL, interleukin; NF-κB, nuclear factor-κB; NLRP3, NACHT, LRR and PYD domain-containing protein 3; T_H, T helper; TLR, toll-like receptor; TNF, tumour necrosis factor.

Bacterial sensing may also be strengthened through the increased expression of toll-like receptor 2 (TLR2) by local macrophages or dendritic cells³⁴. Compared with healthy skin, the microbiome of the skin in HS is altered, with an increase in certain bacterial taxa, including anaerobes, and an overall decrease in microbial diversity⁶⁶. These changes may contribute to the pathogenesis of HS via triggering immune system reactivity and inflammation⁶⁶.

Once secreted, IL-1β and TNF act on various cell types with partially overlapping effects (Figure 6). IL-1β induces the production of chemokines, with the most prominent chemokines attracting neutrophilic granulocytes. TNF activates endothelial cells, causing a stronger expression of adhesion molecules, and stimulates an assortment of chemokines that attract neutrophils, T cell subsets and monocytes into the skin³⁴.

The importance of TNF involvement in the initial pathogenic events of HS is highlighted by patient responses to anti-TNF therapy³⁴

The induction of chemokines and endothelial cell activation leads to an intense infiltration of immune cells into the developing lesions followed by the development of monocytes into macrophages and dendritic cells³⁴.

While their precise role in the pathogenesis of HS has yet to be elucidated, various other cells are also seen to be prevalent in HS lesions, including³⁴:

• Mast cells
• Natural killer cells
• B cells
• Plasma cells

Notably, HS differs from other immune-mediated skin disorders, such as psoriasis, due to the strong expression of the anti-inflammatory mediator IL-10³⁴.

In people with HS who also smoke tobacco, nicotine can increase intracellular cAMP levels, possibly enhancing cutaneous IL-10 production³⁴

Following induction by pro-inflammatory cytokines, such as TNF, IL-10 in macrophages can inhibit immune responses by suppressing monocyte and macrophage pro-inflammatory cytokine production. This leads, both directly and indirectly, to a reduced T-cell activation³⁴.

When does HS progress?

The sequential progression of HS is still poorly understood. However, the events seen in advanced disease can be distinguished from the initial pathogenic events (Figure 7)³⁴.

Figure 7. The progression of hidradenitis suppurativa to advanced disease (Adapted³⁴). AMP, antimicrobial protein; CL, chemokine ligand; G-CSF, granulocyte colony-stimulating factor; IFNγ, interferon-γ; IL, interleukin; MMPs, matrix metalloproteinases; T_H, T helper; TNF, tumour necrosis factor.

As HS progresses, a diverse range of immune cells permeate the skin and secrete specific cytokines³⁴

T cells produce high levels of interferon-γ (IFNγ) and IL-17 in the skin of people with HS, similar to the levels in people with psoriasis. In a previous study, CD4+ T-cell enrichment was shown to secrete IFNγ and IL-17 in ex vivo experiments, implying that T helper (T_H) cells can produce these mediators³⁴.

IL-12 and IL-23 are present within the skin of people with HS. These cytokines support the function of T_H1 and T_H17 cells and can be produced by dendritic cells or macrophages³⁴.

IFNγ activates macrophages and tissue cells, which may be essential for local T-cell activation³⁴

In the HS lesions, the infiltration of immune cells from blood vessels is triggered by the activation of dermal endothelial cells by IFNγ. A positive feedback loop then forms, with IFNγ inducing the secretion chemokines, such as CXCL10, that attract T_H1 cells (Figure 7)³⁴.

Secreted predominantly by T_H17 cells, IL-17 then works synergistically with other tissue-active cytokines, such as TNF, IL-22 and IFNγ, to stimulate the production of specific³⁴:

• Chemokines, such as CCL20, CXCL1 and CXCL8
• Cytokines, such as G-CSF and IL-19
• Epidermal antimicrobial proteins (AMPs)

A reduced expression and action of IL-22 may play an important role in skin destruction and systemic metabolic changes seen in HS. Notably, IL-22³⁴:

• Induces AMPs, especially in the presence of IL-17
• Helps protect tissue cells against cellular damage
• Counter-regulates inflammation-induced metabolic alterations

How do inflamed nodules or abscesses form?

Lowered AMP levels in the lesions result in a reduced ability to inhibit bacterial propagation³⁴. This proliferation of intrafollicular bacteria, in addition to a massive infiltration of immune cells, leads to the rupturing of the dilated hair follicle. Inflammation then increases due to the release of follicular content into the tissue, such as DAMPs, keratin fragments, and bacterial products³⁴.

TNF and IL-1β then induce chemokines that attract immune cells and activate endothelial cells, which allows immune cells to infiltrate the skin. This leads to the formation of subcutaneous inflammatory nodules and dermal abscesses³⁴.

IL-1β induces the production of³⁴:

• Cytokines, such as IL-6 and IL-32
• Extracellular matrix-degrading enzymes, such as matrix metalloproteinases (MMPs)

MMPs facilitate the rupture of adjacent dilated hair follicles and stimulate the destruction of the skin with the formation of physically burdensome abscesses and tunnels³⁴.

IL-36 cytokines are also highly expressed in the lesions, promoting³⁴:

• Neutrophil-attracting chemokines
• AMPs
• Specific cytokines, such as IL-1β and IL-36γ

At the lesion, neutrophils then contribute to the production of inflammatory cytokines and pus formation³⁴.

The neutrophils in HS have an enhanced ability to form neutrophilic extracellular traps (NETs) and the degradation of these NETs is impaired⁶⁷. This is thought to contribute to inflammation and the generation of autoantibodies against DNA, nuclear proteins and NET components, which further trigger aberrant immune responses⁶⁷.

Neutrophils also produce lipocalin 2 and cathelicidin-derived peptide LL37. Lipocalin 2 is a cytokine that induces inflammatory pain and further neutrophil tissue infiltration, forming a positive feedback loop. Cathelicidin-derived peptide LL37 is an antimicrobial peptide that may play a part in T-cell proliferation within the lesions³⁴.

As the tissue disintegrates, pus and follicular stem cells may promote the development of pus-draining epithelialised sinus tracts and fistulas. HS lesions also contain thickened interfollicular epidermis, in addition to inflammatory nodules, abscesses and tunnels³⁴.

The culmination of these activated immunological pathways leads to a lessened antimicrobial defence, the degradation of extracellular matrix, pus formation and pyogenic progressive tissue destruction³⁴.

How do you diagnose HS?

HS diagnosis is based on the nature and location of skin lesions as well as the disease course, which can be defined as persistent (lesions present for at least 6 months) or recurrent (>2 skin lesions occurring or recurring within 6 months)^35,68.

Large international studies have shown that there is an average delay of 7–10 years between the onset of disease and the diagnosis^17,18

Typical HS skins lesions are characterised by purulence, malodorous discharge, pain and discomfort during daily life activities³⁵.

Patients may present with one or multiple types of lesions simultaneously, which typically include⁶⁸:

• Inflammatory nodules
• Abscesses
• Inflamed and draining sinus tracts or fistulas
• Rope-like scarring
• Open comedones
• Bridged scars
• Post-inflammatory double-ended pseudocomedones (resembling a ‘tombstone’)

Lesions generally appear in intertriginous areas or other areas such as the nape of the neck, the axillae, inguinal folds, buttocks, inframammary, or the retroauricular area. However, the location of these lesions in specific areas of the body is influenced by biological sex (Table 1)^15,69,70.

Table 1. Differences in hidradenitis suppurativa lesion prevalence between men and women (Adapted^15,69,70).

A family history can also be used to support the diagnosis of HS accompanied by various additional clinical signs, including recurrent atypical lesions in intertriginous areas, such as folliculitis and open comedones; the presence or history of a pilonidal sinus; and typical lesions in atypical locations, such as the inner thigh or the waist^69,71.

What diagnostics can be used for HS?

Ultrasonography is now considered part of standard of care in HS and is used to identify clinically undetectable lesions, characterise disease severity, as well as guide surgical treatment⁷². Ultrasound machines with upper ranges working on 15–33 MHz can accurately visualise deeper layers of the skin and differentiate between lesional and non-lesional areas, while machines with frequencies up to 70 MHz can detect early subclinical features of HS⁷³. Early signs include hair follicle abnormalities and fluid collection^73,74.

Colour Doppler ultrasonography is reported to detect subclinical features more accurately than standard ultrasonography and can illustrate the surrounding vasculature⁷³.

More advanced imaging modalities that may be used to diagnose HS include:

• Magnetic resonance imaging (MRI): Enables complete body examination, allows differential diagnosis of perianal lesions caused by Crohn’s disease and pilonidal cysts, and may be helpful in preoperative assessment of fistulation in the anogenital area^72,75
• Positron emission tomography and computed tomography (PET-CT): Has been used to identify HS lesions while examining patients for malignancies⁷²
• Reflectance confocal microscopy (RCM): May be used to identify subclinical features of HS as it has exceptionally high resolution and sensitivity but it cannot detect deep cutaneous tissues⁷²

In cases of HS that are uncertain, biopsies can be used to reject other potential disorders, such as pyoderma gangrenosum, squamous cell carcinoma or lymphomas³⁴. However, skin biopsies are not usually required for the diagnosis of HS³⁴.

The type of alteration determines the histopathological characteristics of HS. These can range from early cysts, nodules or abscesses to inflamed sinus tracts or rope-like scars⁷⁶. In ruptured cysts, pan-keratin immunostaining as well as haematoxylin and eosin staining can be used to visualise the keratin fragments and debris that become dispersed in the dermis⁷⁷.

There are alternative diagnostic techniques not typically used to diagnose HS that may prove useful in specific diagnostic scenarios:

• Bacterial cultures: Can be used in cases that are suggestive of infection rather than HS or secondary infection in HS³⁴
• Dermoscopy: Polarised or incident light dermoscopy can be used to provide three-dimensional views of the skin surface and to identify clinical features of HS that may not be evident to the naked eye⁷⁸

A plethora of biomarkers have been proposed as diagnostic indicators of HS, most notably serum interleukin-2 receptor (IL-2R); however, these biomarkers remain to be clinically validated and so are not yet recommended for use in clinic⁷⁹. Click or tap here to enter text.³⁴

How do you classify severity in HS?

A complete body skin examination is necessary to assess the extent and severity of HS³⁴. To classify the extent and severity, this examination can utilise a number of different scores (Table 2).

Table 2. Assessment scores and stages for hidradenitis suppurativa (Adapted³⁴).

Severity scores in HS

The earliest score to be introduced is the Hurley stage scoring system, a widely recognised and rapid classification of disease severity⁸⁰. A more refined version also captures the extent of inflammation as well as distinction of severity within a single stage⁸¹.

Another tool frequently used in clinical trials and daily practice is the Physician Global Assessment (PGA) Tool⁸². As a rigid system that distinguishes only six stages, this tool is validated and easy to use, and also allows for the observation of changes during treatment⁸².

An alternative severity score is the Sartorius system, which provides a benefit over the Hurley stage score by detecting changes in severity over time as well as in response to treatment⁸³. However, this score is labour intensive and is therefore not frequently used in clinical practice⁸³.

A more recently developed tool for the classification of HS disease severity is the International HS Severity Score System (IHS4). This composite score is based on counts of inflammatory nodules, abscesses and draining tunnels, which is then converted into one of three disease stages: mild, moderate or severe⁸⁴.

While useful as a baseline assessment to help make treatment decisions, this score lacks sufficient detail to provide precise descriptions of disease severity or therapy outcomes³⁴. Scores based on lesion counts also fail to take into account extremely inflamed lesions containing indurated areas that lack clearly definable nodules, such as those found in Hurley stage 3 disease^81,85,86.

Ultrasonography scorings

The sonographic staging of severity of HS (SOS-HS) represents a scoring that combines the findings of ultrasound assessment with clinically based Hurley staging to enable better staging of HS⁷³. The SOS-HS considers the number of specific features of lesions, and patients are categorised into stage 1, 2 or 3⁷³.

Recently, a modified SOS-HS (mSOS-HS) has been proposed, which considers the number of affected regions, the number of key lesions such as pseudocysts, fluid collections and tunnels⁷⁴. The mSOS-HS includes four severity categories, stage 1, 2, 3a and 3b, with stage 3b representing people with a very high number of tunnels that may need more urgent treatment⁷⁴.

Another ultrasound-based scoring, the Ultrasound HS Activity Scoring (US-HSA), has also been proposed to assess disease severity and disease progression⁷⁴. The US-HSA considers the corporal regions and subregions in standardised colour Doppler examinations at basal stage and follow-ups, and patients receive a variable score out of a maximum of 18 points⁷⁴.

Patient-reported scores

Patient-reported outcome measures (PROM) have also attracted attention. Commonly used PROMs include the Dermatology Life Quality Index (DLQI), Visual Analogue Scale (VAS), and Numeric Rating Scale (NRS) for pain and itch^87–90.

Biomarkers

As visual assessments of severity do not reliably assess the extent of the disease into deeper skin regions, blood biomarkers have gained increasing interest as an objective assessment of disease activity.

Several proteins have already been identified as being increased in HS, such as chitinase-3-like protein 1⁹¹, matrix metallopeptidase 8 (MMP8)⁹², lipocalin 2⁹³, IL-6^94,95 and C-reactive protein⁹⁵, the expression of which correlate to the extent of inflammatory skin alterations.

Levels of serum amyloid A (SAA) were shown to be significantly associated with the number of nodules, abscesses, fistulas and severe disease, and the study authors have recommended monitoring therapeutic response to prevent disease flares (new or substantial worsening of clinical signs and symptoms)^96,97.

None of the identified biomarkers currently have sufficient clinical validity to be recommended for diagnosing or assessing severity of HS in clinical practice⁷⁹.

Read about diagnostic delay and other unmet needs in HS