IRISH DERM TUTOR

Introduction

Epidemiology

Clinical findings

Pathogenesis

Follicular occlusion and inflammation

Microbiology

Genetics

Other potential triggers

Associations (obesity, smoking, cardiovascular)

? Different phenotypes

Severity assessement scores

Screening suggestions

Management

Self care

Initial management (BAD guidelines)

Next management (BAD guidelines)

Other management considerations

Hidradenitis suppurativa is a chronic, debilitating, and often painful inflammatory skin condition that primarily affects the apocrine-gland bearing regions of the body

The axilla, groin, perineum and inframammary folds are commonly affected

Less common areas affected include the abdominal folds and post-auricular regions

It is characterised by recurrent abscesses, nodules and sinus tracts that can lead to scarring and can have a profound impact on quality of life

Patients tend to have higher rates of depression compared to psoriasis in some studies (43% vs 17%)

Prevalence varies depending on study you look at with an estimated UK prevalence of 1-4%

The estimated Female:male ratio is 3:1

The typical age of onset is in the 2nd-4th decade of life

Men are more likely to develop severe disease

There is increased prevalance among African-American compared to Caucasian populations

There is a definite association with obesity and smoking

HS typically presents with recurrent lesions in intertriginous areas

Open double-headed (‘paired’) commedones are a typical finding that is seen in Hidradenitis Suppurativa

Lesions can then range from isolated papules and nodules to abscesses

In severe forms the lesions can progress to form sinus tracts, fistulae and scarring

The lesions can have a profound impact on a patient’s quality of life

They can be extremely painful and can produce a mucopurulent discharge which can soak clothing and be malodorous

The disease tends to follow a chronic course with cycles of acute flares

When an acute flare occurs the lesions may increase in number and severity with worsening pain, increased drainage and possible restriction of movement

Long term complications include:

SCC in chronic areas of scarring (so should consider biopsying any atypical or vegetative appearing lesion)

Fistula formation (which can affect urethra, bladder or rectum)

Lymphoedema

Chronic anaemia

In short, HS begins with follicular hyperkeratosis and occlusions in apocrine-rich skin folds

Ruputure of the plugged follicles releases keratin, DNA and microbres that drive a prominent innate immune response

The pathogenesis of HS is not fully understood and is complex

It involves a combination of genetic, hormonal and environmental factors

Essentially the primary event of HS appears to be follicular hypkeratosis and occlusion in apocrine-gland rich areas

This leads to rupture of the hair follicle with the release of cellular debris (eg keratin, DNA) and bacteria into the surrounding tissue which triggers an inflammatory response

Increased pro-inflammatory cytokines and other immune mediators are round in HS lesional skin

Some of the key pro-inflammatory cytokines include IFN-γ, TNF-α, IL-1, IL-17 and IL-12/23

Complement dysregulation, abundant neutrophils, increased humoral response (B cells, plasma cells) and dysbiosis is also seen

Overall, it appears to have a much more complex pathogenesis than psoriasis and the inflammation appears to be much more pronounced than in psoriasis

This may account for why treatment of this condition can be very difficult

The chronic inflammatory state can lead to tissue destruction and the formation of abscesses and inflammatory epithelialised tunnels (sinus tracts)

This results in a complex web of tendrils that occur under the skin and scarring

HS is primarily an inflammatory disease and any infection is considered secondary

Bacterial sampling of pus can show no presence of bacteria

Acute superinfection by staphyloccus is rare

Also it is unusual to get lymph node enlargment in the vicinity of lesions despite the inflammation and the presence of bacteria

However, dermal bacteria may be important in further driving the inflammation and disease

Dysbiosis (changes in bacterial composition compared to normal skin bacteria) is commonly observed

A diverse range of bacteria can be seen and lesional skin tends to show a progression from Gram-positive aerobic species to Gram-negative anaerobic species

The sinus tracts are ideal for bacterial remnants to stay and grow and the bacteria may produce biofilms which may contribute to inflammation and the chronicity of the disease

This may contribute to a persistent immune response that may cause further damage in the dermis which may lead to further suppuration, tunnels and fibrosis

20-40% of HS patients report a family history of HS

HS patients with loss of function mutation in gamma-secretase genes (NCTSN, PSEN1, PSENEN) are seen in about 5% of HS cases.

Tends to be seen in Asian families and patients can have a severe, extensive phenotype

Some rare mutations are seen in syndromes (eg PSTPIP-1 in PAPA)

GWAS results are awaited but it appears that many genes seem to be implicated in HS

Mechanical stress:

Is possibly a trigger based on clinical observation but this remains to be proven

This could possibly be related due to damage of follicular outlets

Hormonal factors:

This is still unclear

A female predominance, post-pubertal onset, premenstrual flares and improvement sometimes during pregnancy may imply a role

The complexity of pathogenesis has led to multiple potential targets for treatments including the following:

Approved: Anti-TNFα agents (adalimumab)

Phase 3 trials: Other Anti-TNFα agents, anti IL-17 agents

Phase 2: C5a, JAKis, IL-36 via IL-36R, IL-1, other targets

Obesity:

HS is more prevalent among individuals who are overweight or obese

Obesity may contribute to pathogenesis through subclincial inflammation, metabolic changes and increased friction in skin folds

The risk of obesity is 40% vs 13% compared to age and sex-matched controls (Sabat et al)


Smoking:

Approximately 90% of patients with HS are current or former smokers

Nicotine may contribute to disease in various ways including the induction of epidermal hyperplasia and by influencing bacterial propogation and biofilm formation


Cardiovascular risk:

Compared with controls, patients with HS have significantly increased risk of MI and MACE

Risk of cardiovascular death 58% higher than in patients with severe psoriasis (Egeberg A et al - population cohort based study, JAMA dermatol 2016, n=5964)

IBD:

1% IBD prevalence in Europe

2% HS patient have IBD

16% (1/6) IBD patients attending hospital have HS

Therefore may be useful to screen patients for IBD in HS patients

Other associations include:

Depression

Significant impact on QoL

Significant psychologial impact

A recent study published in Dermatology in 2021 (Anxo Gonzalez-Manso et al) classified two differeent clusters of phenotypes based on two-step cluster analysis (N=103)

Cluster 1 (65%)

• Non-obese males with early-onset HS

• Nodular lesions in posterior sites and history of pilonidal sinus

• Higher IL-10 (anti-inflammatory cytokine), presence of gamma-secretase mtuations

Cluster 2 (35%)

• Obese males or females and later onset

• Lesions in anterior sites

• More sinus tracts and abscesses and less nodules

• Higher IL-1, CRP, IL-17, IL-6

The study suggests that there may be distinct inflammatory pathways between the two clusters

Cluster 1: suggests a possible genetic/developmental component to the disease and may be linked to gamma secretase mutations in cases

Cluster 2: There are higher concentrations of inflammatory markers and this may suggest a more inflammation-driven pathogenesis (activation of the inflammasome). The later onset might suggest environmental factors such as obesity may play a role

But this study is small and needs further research

There are many out there

I will mention the Hurley stage and HiSCR

Others include: Refined Hurley Stage (includes lesion counts), HS-PGA, HS Severity Index (HSSI), International HS severity score (ISH4), Modified sartorius score

Hurley clinical staging -

1:

Abscess formation (single or multiple)

Without sinus tracts and scarring

2:

Single or multiple, widely separated, recurrent abscesses

With sinus tract formation and scarring

3:

Multiple lesions coalescing into inflammatory plaques involving most of the affected region

Issue - not dynamic as it is unusual to go down in grade with treatment

Going up stages is common but going down stages less common (as if tracts/scarring present will not improve with medical treatment only

HiSCR:

Used in clinical trials

Looks to see if criteria has improved relative to baseline:

> 50% reduction in total number of inflammatory nodules

With

No increase in abscess count and no increase in draining fistulae

This is quite a lower bar than what we look for psoriasis patients

Annual - enquire about IBD, spondyloarthritis, sexual dysfunction

As necessary - depression, anxiety, hypertension, DM, Dyslipidaemia, Substance misuse, suicidality

There are BAD guidelines from 2018 (Ingram et al) and there is a very useful algorithm you can use within these guidelines:

Obtain adequate pain relief from GP to help manage acute pain with flares or chronic pain

Avoid tight clothing and synthetic materials (may increase friction)

Obtain wound dressings from GP (for actively pus-producing lesions), incontinence pads may be required

Anti-septic wash (eg chlorhexidine or dermol 500 may help but no definitive evidence)

Record Hurley Stage

DLQI (quality of life)

Do lesion count, ask about number of flares in last month

Measure pain (using VAS) and treat as appropriate

Give an information leaflet (eg BAD)

Offer smoking and weight management referral (if relevant)

Screen for depression/anxiety

Screen for treatment cardiovascular risk factors (Measure BP, Lipids, HbA1C)

Provide dressings for pus-producing lesions

Consider 1% clindamycin (Dalacin T lotion) twice daily to affected skin regions

Oral tetracycline (eg lymecycline 408mg or doxycycline 100mg) once or twice daily x 12 weeks

Consider immedaite clindamycin/rifampicin if Hurley stage III at initial consultatoin

Assess response at 12 weeks

If successful:

Continue with ongoing lymecycline/doxycycline and consider treatment breaks to assess need for ongoing therapy and to limit risk of resistance

If unsuccessful:

Clindamycin 300mg bd and rifampicin 300mg for 10-12 weeks

If unsuccessful:

Consider acitretin (0.3-0.5mg/kg/day) if no child bearing potential or Dapsone

If unsuccessful:

Offer adalimumab 40mg weekly to people (licensed from 12 years old) with moderate-to-sever HS unresponsive to conventional systemic therapy

If unsuccessful:

Refer to HS surgical MDT for extensive excision

Evidence as per Hurley Stage:

Hurley stage 1 considerations:

No real evidence for topical antiseptics but often used
Oral tetracyclines: 40% of patients achieve HiSCR at 12 weeks if have Hurley Stage 1

Topical antibiotics can be useful - eg topical clindamycin 1% bd for 12 weeks was found to be equal to tetracycline in one trial

15% resorcinol used as a peel in Europe often but not available on NHS (85% achieved HiSCR 1 in one study)

Hurley Stage 2:

Consider Clindamycin and Rifampicin

300mg bd each

60% achieved HiSCR in some studies

Consider infliximab 5mg/kg every 8 weeks in people with moderte to severe HS unresponsive to adalimumab

IL corticosteroids for carefully selected individuals with HS in acute phase

Consider metforming with concomitant DM and females with HS and PCOS

Consider extensive excision in people with HS to minimize recurrence rate

Consider extensive excision when conventional systemics failed

Consider secondary intention healing or flap closure (axillary wounds) in people with HS following extensive excision

[Note do not offer isotretinoin unless there is concomitant moderate to severe acneiform lesions face or trunk]

Treatment:

Antibiotics:

Topical (clindamycin 1%):

Tends to be only used for very limited, superficial disease

Although can be used as an adjunct when get flared lesions

Use twice daily for 12 weeks

Tetracyclines:

Clindamycin/Rifampicin:

300mg twice daily (each)

Covers Gram +ve and Gram -ve bacteria

In one small study (n=16) 56% had cleared at 10 weeks

Tips:

If get intolerable side effects change clindamycin (eg to doxy, minocin, clarithromycin, cipro)

If rifampicin causing problems: decrease to 150mg od (and increase as tolerated eg to bd)

Avoid rifampicin as monotherapy

Retinoids:

Acitretin:

Normalises follicular cornification and has anti-proliferative effects on keratinocytes so makes sense it should work in HS

Case series tend to use high doses (50-75mg/day)

Prospective study 17 people: 47% response, 47% drop-out

Can potentially combine it with other agents

Isotretinoin: BAD guidance, don’t use unless have acneiform lesions

Dapsone:

30-40% response rate in small case series

Response can be rapid

Need to monito

Cislosporin:

Poor evidence

50% improved slightly with ciclosporin in a case series

HS III, adding another oral antibiotics:

Oral septrin 960mg bd for 3/12 (monitor)

Oral co-amoxiclav and boosted co-amoxiclav (monitor)

Azithromycin

Tip:

Reserve for rescue/bridging treatments in severe disease by adding to adalimumab or a retinoid

Metformin:

As well as playing role in diabetes it is found to have anti-androgen and anti-inflammatory effects

Max dose 2g/day, usually start 500mg od (GP may titrate up)

Evidence:

Kirby et al 2020, J Derm Treatment.

Retrospective review over 12 months. 53 patients (85% female), mean weight 102kg, dose 1.5g

68% had subjective improvement (19% quiescent on monotherapy)

25% no improvement

Insulin resistance noted in 75% (presence did not predict reponse to metformin)

Tip: consider adding as an adjunct in patients with high BMI, insulin resistance and PCOS

IV antibiotics:

Ertapenem

1g daily x 6 weeks

Reserved for severe disease

One study Sartorius score reduced > 50% (n=30) (Join-Lambert et al. Efficacy of ertapenem in sever HS a pilot study in achort of 30 consecutive patients, J antimirobial, 2016)

Needs Infectious disease input for OPAT

If don’t have ertapenem access other options: ? Ceftriaxone or Taxocin

Issues to consider:

? Resources

? Resistance

Line complications (infection, line occlusion, thrombosis)

? Risk of other drug events (eg blood dyscrasia)

Indications where may consider it:

Acute flare (with aim as a bridge to another treatment)

Pre-biolgoic or pre-surgery

Biologics and potential new agents:

Anti-TNF agents:

Levels of TNF and IL1 are much higher in patients than in psoriasis so anti-TNF agents used

Adalimumab:

Licensed for Hidradenitis suppurativa

NICE June 2016:

For treating moderate to severe HS from 12 years of age

Weekly dosing of 40mg

If disease has not responded to conventioinal systemic therapy

Assess response after 12 weeks, only continue if:

A reduction in 25% or more in total abscess and inflammatory nodule count

No increase in abscesses and draining fistulae

Evidence:

PIONEER study (I and II pooled: n= 633).

HiSCR higher than placebo at 12 weeks (50.6% vs 26.8%)

‘Essentially about 50% of people get about 50% better’

Also placebo effect seems quite high (which seems to be a theme in HS studies)

BJD 2021, Marzano et al: inverse correlation between therapeutic delay and clinical response

BJD 2021, Prens et al: Only about 56% stay on adalimumab at 12 monts (Primary reason is ineffectiveness)

Tips:

Helpful in HS I and II but less so in HS III where multiple treatment approaches needed (Navrazhine et al 2021: IL-17 and tunnels vs Ada and nodules)

Infliximab:

RCCT evidence shows used inconsistently

IN America have more flexibility to increase dose and shorten freuqency if required which may be of some benefit

In UK have less flexibility

Anti-IL 23 agents:

Risanikizumab and guselkumab for HS:

No signfiicant effect seen compard to placebo

Suggests IL-23 blockers not that effective in HS

IIL 17 agents:

IL-17A and F are significantly elevated in HS

TH17 cells can produce IL-17 through IL-23

But Innate lymphocytes (gamma delta T cells and MAIT cells can produce IL-17 independently of IL-23 cells

Secukinumab:

SUNNY studies - pooled analysis

At standard dose or 300mg every 2 weeks both were better than placebo but weren’t great

44% achieved HiSCR (both doses similar effect) compared to 32% placebo

Brodalumab:

IL-17 receptor A antagonist

Ope label studies: 10 patients studied

Surprisingly 100% reached HiSCR 50 at week 12 but authors felt these results were unlikely to be reproduced in future studies

Once weekly or every 2 weeks

IL-1a agents:

IL-1a is overexpressed in HS

Anakinra:

9 active arm, 10 placebo arm

100mg s//c daily vs placebo

HiSCR: 78% anakinra, 30% placebo

Bermekimab:

IL-1a antagonist

Phase II: 42 patients

24- TNF failure, 18 TNF naive

Weekly dosing

HiiSCR at 12 weeks:

61% TNF naive, 58% TNF exposed

No placebo arm

JAK inhibitors:

Multiple cytokine receptors thought to be involve din HS signalling through JAK pathway so it thought that maybe JAK inhibitors would be beneficial

Brepocitinib beat placebo at week 16

Higher doses of JAK inhibitors tend to beat placebo

Overall may be beneficial but effect may be modest

Weight loss:

Weight loss improves HS

Bariatric surgery is most effective but not feasible in all patients

GLP analgoues:

Reduces insulin resistance and may have anti-inflammatory effects

Reduce cardiovascular mortality in diabetic patients

Semaglutide:

Approved for treatment of obesity in patients with BMI > 30 or BMI > 27 and an obesity related complication (? HS)

2.4mg weekly

In randomised controlled trial of non-diabetics (1961 patients)

Mean change in body weight at week 68: 14.9% vs 2.4% palcebo

Liraglutide:

1 case report of efficacy in HS

RCT trial evidence in psoriasis

Surgical management HS:

Mean time from HS diagnosis to surgery almost 13 years

Guidelines suggest it is usually just to treat severe advanced regional disease and that disease is refractory to systemic therapy

BAD guideline: WLE

She believes it should be considered at outset for every patient

Medical management helps inflammatory disease

Surgery helps managing sinus tract disease and scarring

She thinks a combined clinic is very beneficial with plastic surgery

Post-op dressing care int the first 8 weeks necessitates surgery close to home

Buttock disease:

Colorectal surgeons may be best for colorectal disease

A good surgical approach for HS affecting gluteal region -

De-roofing sinus tract

Curettage of lining to remove that stratified squamous epithelium and granulation tissue

This creates a healthy wound bed which can heal by secondary intention

(John Ingram cardiff university website - good video on how to de-roof)

3 aims of surgical management in HS:

Recurrence rates very variable in literature (This is St. Johns and St George’s studies)

1. Acute mx:

I&D - recurrence 100%

2. Local control:

De-roofing and curette sinus tract - can give local disease control or reduce disease burden and give medical therapy a much better chance at working

If extensive de-roofing undertaken they will need an inpatient stay, they can shower at day 2 and go home when pain relief under control

As soon as can manage dressings themselves can get back to work (usually about 2-4 weeks)

Usually healed at about 8 weeks

Recurrence 5%

Limited local excision (+surgical margin)

Can be useful in groin and vulva assuming there is partial medical control has been gained and there is a normal tissue margin around plaque being excised to ensure primary closure

Recurrence 2%

3. Curative:

WLE (+ surgical margin): < 2%

For instance can use in axilla

Day case - Is a one stage reconstruction where sinus tracts are excised down to normal tissue (often down to fascia)

Pilosebaceous unit is removed

Return to work similar to deroofing procedure

(Jemec JAMA 2017)

Complications:

Recurrence

Lymphoedema < 1% (GSTT)

Delayed wound healing

Bleeding (haematoma 1-2%)

Infection < 1%

Numbness < 1%

Recurrence high to low:

I&D (eg peri-anal area)

De-roofing (eg vulvar area)

Limited local excision (eg inferior breast)

WLE reconstructive different closure methods can be done:

Flaps

Skin grafts

Secondary intention (May use negative VAC dressing which patient can use at home)

Other types surgery:

Breast reduction and lifts (affected tissue excised and breast lifted removing that occlusive element to the disease)

Abdominoplastys

Can be difficult to get funding for both

Ideal surgical candidate hard to find in HS patients: Slim, non-smoker, disease confined to axilla where cure can be achieved

Factors impacting surgery:

Hurley stage

Size of defect

Anatomical area

Scar location

10:30

Patient RF:

BMI - ideally should be < 35 (>40 risks are outweighed so refer patient for help with weight loss when meet patients)

Smoking status (+ CV risk)

Degree of inflammation - established medical therapy and/or pre-surgery IV abx

Surgeon will often like inflammation to be reduced pre-surgery

Ertapenem (30 consecutive patients - 9 were pre surgery)

Benefits of weight loss 4 fold in HS patients:

Decrease

Medical weight loss:

Orlistat (GP)

GLP-1 agonists

Liraglutide

Surgery for HS:

Adalimumab

Half life is 10-20 days (up to 6 weeks)

SHARP study

Significantly more acheived HisSCR at week 12 if on biologic

There was no increase in post op complications

Shanmugam et al: Significant improvement in HS surgery with biologics beforehand.

Dr. Lamb feels timing of biologic prior to surgery could be important

Pre-op:

Need to optimise

May need to correct anaemia

Correct low albumin

Avoid de-rooofing in flexural sites especially genital area

Summary:

Single site - potetnially curative

Multi-site: reduce sidease burden/ Increase efficacy medical teharpy

Early referral imporant - paralell with medical treatment (+BMI)

MDT meetings great if possible

Optimise weight, anaemia, a

Management:

Some guidelies where Americans use prednisolone for HS

She rarely uses it but have ‘PG like HS’ which looks very inflammatory then she may

References:

1. González-Manso, A., Agut-Busquet, E., Romaní, J., Vilarrasa, E., Bittencourt, F., Mensa, A., Cantó, E., Aróstegui, J.I., & Vidal, S. (2021). Hidradenitis Suppurativa: Proposal of Classification in Two Endotypes with Two-Step Cluster Analysis. Dermatology, 237(3), 365-371. doi: 10.1159/000511045​1​.

2. Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K. Hidradenitis suppurativa. Nat Rev Dis Primers. 2020 Mar 12;6(1):18. doi: 10.1038/s41572-020-0149-1. PMID: 32165620.

3. Ingram, J.R., Collier, F., Brown, D., Burton, T., Burton, J., Chin, M.F., Desai, N., Goodacre, T.E.E., Piguet, V., Pink, A.E., Exton, L.S. and Mohd Mustapa, M.F. (2019), British Association of Dermatologists guidelines for the management of hidradenitis suppurativa (acne inversa) 2018. Br J Dermatol, 180: 1009-1017. https://doi.org/10.1111/bjd.17537

4. Egeberg A, Gislason GH, Hansen PR. Risk of Major Adverse Cardiovascular Events and All-Cause Mortality in Patients With Hidradenitis Suppurativa. JAMA Dermatol. 2016 Apr;152(4):429-34. doi: 10.1001/jamadermatol.2015.6264. PMID: 26885728.