1

Hidradenitis Suppurativa: The Study of Natural History,

Genetics, Comorbidities and Impact on Patient’s Life

A thesis submitted to McGill University in partial fulfillment of the

requirements of the degree of Master of Science (M.Sc.) in Experimental Medicine Division

By

Abdulhadi Jfri

McGill University, Montreal, QC, Canada

Date of submission: February 2020

© Abdulhadi Jfri (2020)

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Acknowledgments

First and foremost, I would like to say thank you to my family for their loving

supporting me and encouraging me throughout this year.

I thank my supervisor, Dr. Ivan Litvinov, for his continued support and teaching

throughout my Master. I learned a lot from him and still learning. He is the best

mentor that I could ever ask for. Thank you for your unending kindness and

optimism. Thank you for encouraging me to explore, try and publish more.

I owe thanks to both Dr. Elena Netchiporouk and Dr. Elizabeth O’Brien for helping

me and advising me in this project over the year.

I also thank the members of my supervisory committee, Dr. Denis Sasseville and Dr.

Simon Rousseau, for their support. Thank you to McGill University for having given

me this opportunity to do my master during my dermatology residency training.

Finally, I would like to thank all the hidradenitis suppurativa patients for being

generous and giving me a lot of their valuable time to complete all the lengthy study

surveys and forms.

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Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder. It affects

around 1-4% of people worldwide. A genetic component in the pathogenesis is

highly likely considering that ~30-40% of patients with HS report a family history

of the disease. HS has a great impact on the patient’s quality of life. Depression is

prevalent in HS and around 19-27% in our cohort screened positive for depressive

symptoms with unknown depression diagnosis. HS affects work with presenteeism

being more prevalent than absenteeism and is most impacted by work location.

Hurley staging was the most predictive tool for HS absenteeism/presenteeism.

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Résumé

L'hidradénite suppurée (HS) est un trouble cutané inflammatoire chronique. Elle

affecte environ 1 à 4% des personnes dans le monde. Une composante génétique

de la pathogenèse est très probable si l'on considère que ~ 30 à 40% des patients

atteints de HS rapportent des antécédents familiaux de la maladie. HS a un grand

impact sur la qualité de vie du patient. La dépression est répandue dans l'HS et

environ 19 à 27% dans notre cohorte ont été testés positifs pour les symptômes

dépressifs avec un diagnostic de dépression inconnu. HS affecte le travail avec le

présentéisme étant plus répandu que l'absentéisme et est le plus touché par le lieu

de travail. La mise en scène de Hurley était l'outil le plus prédictif de l'absentéisme

/ présentéisme HS.

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Table of Content

I. Introduction …………………………………………………………….8

II. Hidradenitis Suppurativa: Comprehensive Review of Predisposing

Genetic Mutations and Changes……………………………………...19

III. Novel Variants of MEFV and NOD2 Genes in Familial Hidradenitis

Suppurativa …………………………………………………………...39

IV. Psychosocial Impact of Clinical Severity on Hidradenitis

Suppurativa …………………………………………………………...46

V. Impact of Clinical Severity on Work Productivity in Patients with

Hidradenitis Suppurativa …………………………………………….68

VI. Discussion………………………………………………………………86

VII. Conclusion and summary……..………………………………………88

VIII. List of abbreviations ………………………………………………….89

IX. References ……………………………………………………………..92

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PREFACE

Contribution of Authors

Abdulhadi Jfri prepared the study proposal of HS and obtained the IRB approval to conduct the

clinical study under the supervision of Dr. Litvinov. Next, he designed the recruitment forms, and

started recruited patients at Dr. O’Brien’s clinic under her clinical supervision. All data sheets

were entered and analysed by Dr. Jfri who wrote all the chapters, I. introduction, II. Hidradenitis

Suppurativa: Comprehensive Review of Predisposing Genetic Mutations and Changes, III. Novel

Variants of MEFV and NOD2 Genes in Familial Hidradenitis Suppurativa, IV. Psychosocial

Impact of Clinical Severity on Hidradenitis Suppurativa, and V. Impact of Clinical Severity on

Work Productivity in Patients with Hidradenitis Suppurativa.

Dr. O’Brien is the staff running the HS clinic at the MGH who reviewed the data collecting sheets

to make sure, patients’ data were collected accurately.

All the manuscripts have been reviewed by Dr. O’Brien, Dr. Netchiporouk and Dr. Litvinov. Dr.

Litvinov reviewed the statistical analyses and discussion. Dr. Netchiporouk reviewed the

introduction, results and genetic mutations. Dr. O’Brien reviewed the final version of the all the

chapters. In addition, Dr. Alavi, an HS expert from University of Toronto reviewed chapter II.

Comprehensive review of predisposing genetic changes. and contributed to the paper by adding

figure 1.

Chapter I. introduction. Abdulhadi Jfri did the literature review to prepare the study proposal on

HS and summarized it in chapter I.

Chapter II. Comprehensive review of predisposing genetic changes. Abdulhadi Jfri collected

all genes published in patients with hidradenitis suppurativa, pathogenesis classification design

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was suggested by Dr. Netchipoourk who reported the results of the review. Figure 2 was designed

by Abdulhadi Jfri and Dr. Alavi contributed to figure 1.

III. Novel Variants of MEFV and NOD2 Genes in Familial Hidradenitis Suppurativa. Dr.

Jfri interviewed the family with HS. Dr. Netchiporouk suggested testing the family for

autoinflammatory panel given reported mutations in the literature exist in familial HS. Dr. Jfri

filled the genetic test forms, sent for genetic testing and reported the result in the manuscript.

IV. Psychosocial Impact of Clinical Severity on Hidradenitis Suppurativa. Abdulhadi Jfri

collected the data from the HS clinic, performed data entry, and did the statistical analysis (the

tests were suggested by Dr. Netchiporouk and Dr. Livtinov). Dr. Jfri wrote the manuscript and

reported the findings.

V. Impact of Clinical Severity on Work Productivity in Patients with Hidradenitis

Suppurativa. Abdulhadi Jfri collected the data from the HS clinic, performed data entry, and did

the statistical analysis (the tests were suggested by Dr. Netchiporouk and Dr. Livtinov). Dr. Jfri

wrote the manuscript and reported the findings.

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I. Introduction

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease characterized by persistent

or recurrent flares of inflamed painful nodules, sinuses and scars in the axilla, groin or both. (1, 2).

The prevalence of HS ranges between 0.1% - 4% worldwide. (3, 4) HS tends to affect females 3

times more than males. (5, 6) Disease usually starts after puberty, early in the third decade of life.

Prepubertal onset is rare and is associated with positive family history and more severe phenotype.

(7) The diagnosis of HS takes on average around 7 years. (8) This delay is primarily due to the

lack of awareness about HS among non-dermatologist physicians. Smoking and obesity are

common comorbidities in HS patients along with diabetes, Crohn’s disease and polycystic ovary

syndrome. (9-11) Over the years, several clinical parameters have been found associated with a

worse disease activity including male gender, younger age at disease onset, obesity, smoking, and

areas of involvement localized to axillary, perianal and mammary folds. (10)

HS has a great impact on the patient’s quality of life. The pain from the inflamed nodules is the

major complain of patients suffering from HS that leads to the need to take prolonged or frequent

sick leave from work or school. It was found that HS has a great emotional impact on patients and

promotes isolation due to fear of stigmatization (12) The foul smell of the HS lesions can be very

embarrassing and often lead to social withdrawal and isolation. (13, 14) The risk of depression

among patients with HS ranges between 9 -39%. (15-17) There is a higher prevalence of depression

and anxiety in HS patients compared with the general population. (18) Investigating patient’s

sexual health, Kurek et al. found that patients with HS have a significantly higher impairment of

sexual health compared to age-, sex- and body mass index-matched controls. (19)

Given its propensity to cause chronic inflammation and non-healing wounds it is not surprising

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that HS is associated with significant complications. There is a risk of squamous cell carcinoma

(SCC) in long standing lesions of HS. Multiple reported cases and a case series of patients with

HS developed SCC. (20) Strictures, contractures and fistula formation are another example of local

complications. (21) In addition, due to systemic inflammation, HS increases the risk of secondary

systemic amyloidosis, anemia of chronic disease as well as cardiovascular comorbidities. (22)

Unfortunately, the treatment of this debilitating disorder remains suboptimal despite the discovery

of repurposing medications such as TNF-a inhibitors such as adalimumab. Most society guidelines

recommend management strategies based on Hurley staging. (23)

II. Pathogenesis

The pathophysiology of HS is not fully understood. However, the initial step in HS pathogenesis

is thought to be occlusion of the hair follicle. (24-26) The occlusion of the follicle results from

the infundibular keratosis and hyperplasia. (27) Eventually the hair follicle ruptures, followed by

a massive local immune response, resulting in painful inflammation, abscess formation, and in

later stages, sinus tract formation and scarring. (28) Keratinocytes dysfunction and impaired

ceramides productions were also described in the pathogenesis of HS. (29, 30) In fact,

sphingomyelin and ceramide which are both sphingolipids - a group of lipids containing the

sphingolipid base - have structural and biologic functions in the epidermis, and deficiency of

these compounds may contribute to barrier disruption leading to inflammation. In addition,

several of the enzymes involved in ceramide generation may activate natural killer (NK) cells,

type of lymphocyte (a white blood cell) independently (30). Further, Hotz et al. showed that

keratinocytes in HS patient may be intrinsically prone to inflammation and aberrant production

of certain human protein known as gamma induced protein (IP-10) and chemokine ligand 5

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(CCL5). This continuous subclinical inflammation could favor follicular plugging and cyst

production.(29) The expression of several antimicrobial peptides (AMPs) also known as host

defense peptides (HDP) which are part of the human innate immune response have been shown

to be altered in HS (31-36). Expression of AMPs correlated with Il-22 expression in one

study.(37) Commensal bacteria lead to an increased expression of keratinocyte derived AMPs

such as human beta-defensin (hBD) 2 and 3. While protective against bacterial and dermatophyte

infections, genetic overexpression of those peptides contributes to the inflammatory state of HS

(34). Interestingly, despite predisposing patients to HS the degree of overexpression of AMPs

such as hBD-3 and ribonuclease 7 inversely correlated with clinical disease severity emphasizing

the importance of innate immunity and microbiota interaction in disorders like HS (35).

Around 30-40% of patients with HS report a family history which supports a genetic component

of the disease. (38) A genetic mutation with probable autosomal dominant transmission has been

attributed to 5% of patient with HS. (39) Gamma-secretase mutation can result in a severe

phenotype of HS. Gamma-secretase is an intramembranous endoprotease complex composed of

four hydrophobic proteins: presenilin, presenilin enhancer-2, nicastrin, and anterior pharynx

defective. The enzyme can cleave multiple type-1 transmembrane proteins including Notch

receptors. Most mutations found so far in gamma-secretase affected nicastrin that is involved in

the integration of the different subunits into the gamma-secretase complex and in complex

stabilization. (40) Occasional mutations in nicastrin, presenilin 1, presenilin enhancer 2 were

reported. In addition, PSTPIP1 gene has been found to cause PASH (Pyoderma Gangrenosum,

Acne, HS) and PAPASH (Pyoderma Gangrenosum, Acne, Pyogenic Arthritis, HS) syndromes.

PSTPIP1 has recently been found to be a negative regulator of the inflammasome (leading to

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production of IL1 β). Mutations in the inflammasome pathway give rise to various

autoinflammatory disorders. Interestingly, PSTPIP1 is also cleaved by the γ-secretase complex

or its associated downstream mediators and these may be the link between γ-secretase sequence

variants and the inflammasome. POFOUT 1 and NOD2 have been indentified as well (41)

III. Clinical assessment

The Dermatology quality of life index is a validated tool that has been used since 1994 to assess

the effect of the dermatology disorder on the patient’s quality of life and it has been used in patients

with HS. It is a 10-question questionnaire that grades from 0 (i.e., no effect on the patient’s life)

to 30 (the disease has an extremely large impact on the patient’s life). (42) Since HS is a painful

condition, the visual analog scale (VAS) score can be used to grade the intensity of the pain

objectively on a unidimensional scale from 0-10. (43)

Classification of HS severity.

The first severity classification of HS proposed by Hurley in 1989 is routinely used in the clinical

setting to categorize patients into 3 stages based mainly on the presence of sinus tracts and scarring.

Stage II differs from stage I by the presence of sinuses and stage III is given to the patient when

there are multiple interconnected abscesses. It was originally designed for selection of the

appropriate treatment modality in a certain body location (medical therapy for Hurley stage I, local

surgery for Hurley stage II and wide surgical excision for Hurley stage III).(44)

The Hidradenitis suppurativa physician global assessment (HS-PGA) has 6 categories that range

from clear (0 lesions) to very severe (over 5 abscesses or draining fistulas. This system is based

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on the number of abscesses, draining fistulas, inflammatory and non-inflammatory nodules,

however it does not consider the number of body regions involved. This scoring system is very

useful in observing the progression of the inflammation. (45)

The Severity Assessment of Hidradenitis Suppurativa (SAHS) score is a novel staging system

that combines three physician-rated items with two patient-reported items. The physician-rated

items were included: number of involved regions (axilla left, axilla right, submammary left,

submammary right, intermammary or chest, abdominal, mons pubis, groin left, groin right,

genital, perianal or perineal, gluteal left, gluteal right, and others [eg, neck, retroauricular]),

number of inflammatory and/or painful lesions other than fistula (ILOF), and number of fistula.

The 2 patient-reported items were: number of new boils or number of existing boils, which flared

up during the past 4 weeks and the current severity of pain of the most symptomatic lesion in the

course of their daily activities (e. g, sitting, moving, or working) on a numerical rating scale

(NRS-11) ranging from 0 to 10.

Score 0 is given when there are 0 regions involved, ILOF, 0 fistula, 0 new or flared existing boils

in the past 4 weeks and 0-1 NRS for pain severity. Score 1 given to 1-2 regions involved, ILOF

1-4, fistula 1-2, new or flared existing boils in the past 4 weeks 1-2, and NRS of pain severity 2-

4. Score 2 for represents 3-4 regions involved, ILOF 5-9, fistula 3, new or flared existing boils in

the past 4 weeks 3-4, and NRS of pain severity 5-6. Score 3 represents ≥5 regions involved,

ILOF ≥10, fistula ≥4, new or flared existing boils in the past 4 weeks ≥5, and NRS of pain

severity ≥7. Mild disease is defined as an SAHS score of 4 or less, moderate is defined as an

SAHS score of 5 to 8, and severe disease is defined as an SAHS score of 9 or more. the SAHS

score is not based on the identification of different inflammatory HS lesions (e.g., inflammatory

nodule vs abscess) because such a differentiation can present a challenge in daily clinical routine

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for some patients with HS, and its clinical impact is questionable. Thus, the SAHS score simply

differentiates be- tween ILOF and fistula. The proposed SAHS score differs significantly

between the 3 Hurley groups. (46)

Assessment of Psychological aspect and patient’s life

Patients with HS have major body image impairment, which might lead to depression and

anxiety. (47) Self-reports showed significant levels of depression, anxiety and impaired quality

of life. (48) The prevalence of major depression in HS patients has significantly increased from

8.5% to 15.7% over 27 years (1987-2014). (49)

Beck depression inventory-21 items (BDI-21) is one of the most commonly used tools to assess

depression and grade it. (50). A score up to 10 is considered normal, 11-16 is mild mood

disturbance, 17-20 borderline clinical depression. 21-30 moderate depression, 31-20 severe

depression, over 40 is extremely severe depression. Advanced clinical stage and anogenital

location of disease had the greatest impact on the patient’s psychosocial status in one study. (16).

In the literature, there is only one small study assessed depression using BDI-21 of 26 HS

patients showed mean total BDI-21 score was around 10. However, the majority of patients were

having mild-moderate disease with only 2 severe cases and the sample size is very small. The

emotional and the psychological impact of HS on patients have increase the risk of opioid,

cannabinoids and alcohol abuses. (51)

Management of Hidradenitis Suppurativa

a. Medical

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Topical clindamycin 1% has been shown to be effective in a double blinded trial of 27 patients

with mild HS. (52) Systemic tetracycline with doxycycline being the most commonly prescribed

antibiotic for HS shown to be beneficial. (53) Multiple studies demonstrated a beneficial effect

with the use of 10-week course of oral clindamycin combined with rifampin. (54-56) Another

proposed combination is the use of Rifampin-Moxifloxacin-Metronidazole. (57) Intralesional

injection of the inflammatory nodules with triamcinolone acetonide 5-10 mg/ml provides a faster

reduction in the local inflammation and reduces the pain. (58) Matusiak et al reported a

significant clinical improvement in hidradenitis suppurativa clinical severity index (HSSI) and

DLQI score after 1 month of using oral acitretin. (59) Another oral retinoids is isotretinoin that

shown to be effective in females with milder HS not severe Hurley stage III (60) Other orals

such as oral zinc with topical triclosan, an antimicrobial cleanser (61) oral dapsone (62).

Recalcitrant severe cases may respond to oral immunosuppressive such as cyclosporine (63), less

to oral methotrexate (64) or IV ertapenem (65) or linezolid (66)

b. Biologics

Recently biologic molecules have shown promise in controlling the inflammation in HS. Anti-

TNF alpha inhibitors such as adalimumab and infliximab are shown to be very effective in the

treatment of moderate to severe HS. (67-69) The combination of adalimumab with antimicrobial

therapy was found to be superior to adalimumab alone.(70) and adding methotrexate to

adalimumab was more effective than adalimumab alone. (71) Other promising molecules include

ustekinumab (72), anakinra, (73) apremilast (74), secukinumab (75), ixekizumab (76) MABp1

(bermekimab) (77) guselkumab (78) and ongoing trials on IFX-1 and efalizumab.

c. Surgical

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Surgical intervention by local excision of the draining sinuses. (79) or total removal of the

apocrine glands bearing skin can be curative in some cases. (80)

d. Lasers

Carbon dioxide laser can be used to excise the skin. One report described a randomized

controlled trial of 61 patients with HS treated effectively with carbon dioxide laser. (81) Based

on the fact that the pathogenesis of HS occurs within the hair follicle, hair removal types of

lasers like Nd:Yag laser have been shown to reduce the clinical severity of HS and to maintain

the effect for months after the treatment sessions (82, 83)

Purpose/hypothesis of the study

We proposed a study where we planned to better assess the psychological impact of HS on patients

and on their quality of life. As well, as a secondary aim of this study, was to study the natural

history of HS by looking at the prevalence, disease associations, clinical severity among different

stages of HS.

Specific aims and anticipated results

All information gathered from HS patients attending the Hidradenitis Suppurativa (HS) Clinic at

the Montreal General hospital (MGH). HS clinic is monthly and weekly specialized clinic at the

dermatology department of the MGH. Enrolled patients have been evaluated each visit by using

clinical scoring systems to assess their clinical severity (HS-PGA score and Hurley staging

system) (28, 30), pain (VAS score) (29), SAHS (46), quality of life (DLQI score) (27) and Beck

depression inventory (BDI-21 questionnaire) (50). We enrolled so far 131 patients from different

Hurley staging severity. Ethical approval was obtained from the McGill University Health

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Centre. Only patients willing to participate were enrolled in the study after signing the informed

consent.

This study provided data on the prevalence of HS at the MGH, the associated life style

behaviors, associated medical conditions, assessment of the clinical severity, prevalence of

depression and the impact on patient’s life.

Description of study population, inclusion and exclusion criteria

Adult patients diagnosed with Hidradenitis Supprativa (HS) attending the HS clinic at the

dermatology department of the Montreal General Hospital were invited to participate in the study

in accordance with the IRB protocol.

Design and description of methodology and materials

All patients were enrolled in accordance with the IRB protocol. All patients with new or existing

diagnosis of Hidradenitis Suppurativa, who are coming for a regularly scheduled visit, were

offered to participate in the study. Individuals who agreed to participate and signed the informed

consent form were asked detailed history and answered a 10-question questionnaire about

Dermatology quality of life index form (DLQI) (27) and 21-Beck depression inventory

questionnaire (50) and visual analog score (VAS) score for pain (29) and undergone physical exam

for staging and to assess the clinical severity by using Hurley staging system (30), Hidradenitis

Suppurativa physician global assessment (HS-PGA) (28), SAHS (46) by a Dermatology resident

or a Dermatology staff physician.

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Definition of end-point: Each participant agreed to enrolled in the study was required to

complete one visit with the complete assessment described above.

Details on confidentiality.

The investigators took measures to protect the privacy and security of all patient personal

information. Medical information created by this study was entered in a password protected

database. Study files in the database or elsewhere was coded and not labelled with patient name or

medical records number. The code linking patient’s name to a file in the database kept in a safe

location (such as an investigator’s safe in an office for a paper form or a separate password

protected database stored on a restricted access computer in the Division of Dermatology).

At all times, a coded number was used, and no identifiable information was released. Some

results of this study was published in a peer-reviewed research journal. Patients were not

identified in any publication. Patient identifiers will not be made available to other hospitals,

insurers or agencies.

Statement on ethical considerations.

Study was conducted according to ethical principles stated in the Declaration of Helsinki,

ethics approval was obtained for this research study, consent forms was taken into consideration

the well-being, free-will and respect of the participants, including respect of privacy.

In the next chapter, we tried to understand the genetic aspect of HS pathogenesis. Therefore, we

reviewed the current literature on all the reported mutations in sporadic and familial HS cases.

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Furthermore, we tried to find a possible link between those defective genes and the development

of HS lesions.

II. Hidradenitis Suppurativa: Comprehensive Review

of Predisposing Genetic Mutations and Changes

Abdulhadi H. Jfri1, Elizabeth A. O’Brien1, Ivan V. Litvinov1, Afsaneh Alavi2, Elena Netchiporouk1

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J Cutan Med Surg. 2019 Sep/Oct;23(5):519-527. doi: 10.1177/1203475419852049. Epub 2019

Jun 6.

1Division of Dermatology, McGill University Health Centre, Rm. L8-201, 1650 Cedar Avenue,

Montreal, QC H3G 1A4, Canada

2Division of Dermatology, University of Toronto, Women’s College Hospital, 76 Grenville St,

Toronto, ON M5S 1B2, Canada

Keywords: Hidradenitis suppurativa (HS), acne inversa (AI), genes, genetic, genotype

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder. A genetic

component in the pathogenesis is highly likely considering that ~30-40% of patients with HS report

a family history of the disease. The genetic mutations related to HS that have been reported to date

suggest that HS can be inherited as a monogenic trait, due to a defect in either the Notch signaling

pathway or inflammasome function, or as a polygenic disorder resulting from defects in genes

regulating epidermal proliferation, ceramide production, or in immune system function. This

review provides a summary of genetic mutations reported in patients diagnosed with HS and

discusses the mechanisms by which these genes are involved in its pathogenesis.

Introduction

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin

disorder characterized by persistent and/or recurrent inflamed painful nodules, tracts, tunnels,

and scars. It is commonly seen in skinfolds such as the axilla and groin. (1,2) HS is a relatively

prevalent disease (0.1% to 4% worldwide) with a severe impact on the quality of life

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and a host of metabolic, inflammatory, and psychological comorbidities. (3-5)

The pathogenesis of HS is not fully understood, although the initial step in the disease appears to

involve follicular hyperkeratosis, occlusion, cyst formation, and eventual cyst rupture, leading to

a massive inflammatory response and typical clinical findings. (6-9) A positive family history

has been noted in approximately one-third of patients, implying a genetic basis for the disease.

(10) Pink et al found that less than 7% of cases exhibited a monogenic mutation with autosomal

dominant inheritance, usually involving Notch or prolineserine-threonine-phosphatase-

interactive protein 1 (PSTPIP1) signaling pathways. (11) Additional cases have been reported in

association with a variety of genetic skin conditions. (3) In the remaining cases, HS is seen as a

complex, environmentally triggered disorder in a genetically predisposed host.

Alterations in multiple genes involved in epidermal barrier function and/or inflammation appear

to contribute toward this predisposition (Figure 1). In addition to genetics, obesity, smoking, and

hormonal imbalance are contributing factors for HS onset and severity.1 In this review, we

discuss several relevant genetic pathways that may play a role in HS pathogenesis.

Evidence for Monogenic Causes of HS

Monogenic inheritance of HS is rare and can be summarized into 1) defects in Notch and γ-

Secretase signaling pathways leading to a severe comedone-predominant HS phenotype

and 2) defects in inflammasome function resulting in an inflammatory phenotype of HS with

additional systemic features such as arthritis.

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Defects in Notch and γ-Secretase Signaling Pathways

Notch 1-4 are cell surface-embedded receptors that bind ligands on neighboring cells. The

intracellular domain of Notch must be cleaved by γ -Secretase complex for signal transduction to

occur (Figure 2A). Once active, Notch enters the nucleus and transactivates the expression of

genes involved in epidermal and follicular differentiation and proliferation. (12,13) Alterations in

Notch signaling may also arise from genetic inactivation of γ -Secretase, a transmembrane

protease consisting of 4 protein subunits: 1 catalytic presenilin (PSEN) subunit and 3 cofactor

subunits: presenilin enhancer-2 (PSENEN), nicastrin (NCSTN), and anterior pharynx defective-1

(APH1). It facilitates cleavage of membrane proteins including Notch and amyloid precursor

protein (APP) (Figure 2A). In animal models, both deficiency of γ - Secretase and inhibition of

Notch produce a phenotype comparable to HS in humans with abnormal follicular keratinization,

epidermal hyperplasia, cyst formation, andmmabsence of sebaceous glands. (14-16)

In 2006, Gao and colleagues identified a locus of interest on chromosome 1p21.1-1q25.3 in a 4-

generation Chinese family of HS patients. It was associated with a mutation in the γ -secretase

pathway and was later confirmed in multiple other families. (13,17-22) These patients present

with a severe phenotype of the disease. (20) Further studies have identified 41 sequence variants

in the γ-Secretase pathway, of which 30 involve the NCSTN gene, which is critical to integrate

and stabilize the different subunits of the γ-Secretase complex.

Occasional mutations have been reported in PSEN and PSENEN. (23-25) Furthermore, impaired

Notch signaling contributes to aberrant inflammation and immune defenses in HS because it fails

to suppress the innate immune system and alters the generation of natural killer cells. (23,24) In

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recent years, there have been several reported cases of syndromes associated with HS, frequently

involving Notch downregulation. Mutations in PSENEN and protein O-fructosyltransferase 1

(POFUT1) were reported in patients with concomitant Dowling-Degos disease and HS. (26-30)

POFUT1 adds O-fucose to Notch1 receptor, and this step is necessary for Notch signaling

activation. Mutation in the POFUT1 gene decreases Notch activity. (27,31,32) γ-Secretase

cleaves APP and Notch receptor. The products of APP cleavage are stimulators for keratinocyte

proliferation that lead to the follicular plugging phenotype seen in patients with Down syndrome.

(33-35)

The high prevalence of obesity (odds ratio [OR] 3.45) and smoking (OR 1.91) among HS

patients makes them important acquired factors in the pathogenesis of the disease.36-38

Interestingly, acquired Notch downregulation was reported to occur in smokers and Notch

signaling has recently been highlighted as a key regulator of metabolism and metabolic

syndrome. (39,40) Furthermore, hyperandrogenism and polycystic ovarian syndrome have also

been suggested to play a role in the disease pathogenesis in female HS patients. (1) Data from

human and animal studies point toward the importance of Notch signaling in the normal

development and function of the ovaries. In a knockout mice model, Notch2 deletion was

sufficient to induce a polycystic ovarian syndrome phenotype. (41) Although the exact

pathogenic link between HS and its frequent comorbidities is not fully established, this acquired

alteration in Notch signaling may represent a plausible explanation and warrants further

investigation.

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Defective Inflammasome Function

The inflammasome is an intracellular protein complex essential for the control of the innate

immune system. It classically consists of a microbial or damage-sensing protein of the

NOD-like receptor, ex: NLRP3 (NLR) family and a downstream effector, caspase-1. Caspase-1

activation processes pro-IL1β into its active form (Figure 2B). (42,43) Excessive amounts of

IL1β trigger an uncontrolled activation of innate immunity and neutrophil recruitment, causing

end-stage organ damage. (44) Defective inflammasome function is recognized as a central driver

for many autoinflammatory disorders. Autoinflammatory disorders encompass a heterogeneous

group of conditions characterized by the dysregulation of the innate immune system and

clinically manifesting as recurrent/ chronic sterile inflammation in the absence of infection,

allergy, or autoimmunity. (45) Prototypes include cryopyrin associated periodic fever

syndromes, encoded by a nucleotide- binding domain leucine-rich repeat-containing protein 3

(NLRP3) mutation, and Familial Mediterranean fever (FMF), stemming from an MEFV

(Mediterranean fever gene) mutation. These mutations result in aberrant activation of the

inflammasome. (46) The association of HS with autoinflammatory

diseases, including FMF (caused by an MEFV mutation), has been described. (47)

Several syndromes have been detailed that include hidradenitis and other well-recognized

autoinflammatory diseases: pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA)

syndrome is an autosomal-dominant monogenic autoinflammatory disease caused by a gain of

function mutation in the PSTPIP1 gene and is characterized by neutrophilic infiltrates in various

tissues. Together with pyrin (encoded by the MEFV gene), PSTPIP1 is involved in assembly of

the inflammasome (Figure 2B). When mutated it causes high IL- 1β production and leads to

upregulation of caspase-1 activity. This triggers the release of proinflammatory markers,

24

producing a neutrophil-mediated autoinflammatory response. PSTPIP1 is also cleaved by the γ-

Secretase complex and its downstream mediators, providing a potential link between

γ-Secretase function and the inflammasome. (3) If in addition to the above clinical findings of

PAPA syndrome.

HS is also present, the new variant is termed pyogenic arthritis, pyoderma gangrenosum, acne,

suppurative hidradenitis (PAPASH) or pyoderma gangrenosum, acne conglobata, hidradenitis

suppurativa, axial spondyloarthritis (PASS) syndrome. (48) If there is no associated arthritis, the

term pyoderma gangrenosum, acne, suppurative hidradenitis (PASH) syndrome is used. In PASH

syndrome mutations have been reported in the Notch signaling pathway (NCSTN), NOD2,

MEFV, NLRP3, NLRP12, PSTPIP1 (inflammasome function), and Lipin 2 (LPIN2 ). (45,48-50)

In addition to rare cases of autoinflammatory disorders, increased inflammasome function and

levels can be induced by smoking and obesity. (51,52) In fact, it is thought that lipocyte- induced

NLRP3 overexpression is an important driver of insulin resistance, cardiovascular comorbidity,

and increased obesity-associated cancer risk. (53,54)

Evidence for Polygenic Pathogenesis of HS

Familial clustering of HS suggests a polygenic predisposition to HS. Candidate genes include

key regulatory factors in epidermal homeostasis, and activation of both the innate and acquired

immune systems.

Genes Involved in Epidermal Proliferation, Barrier Function, and Homeostasis

Sphingolipids. Sphingolipids are membrane lipids regulating subdomain structure and fluidity of

the epidermal lipid bilayer. (55) In mouse hair follicles, decreased ceramide in sebaceous glands

25

results in solidified sebum, blocked hair shafts, and progressive hair loss. (56) Decreased

ceramide and sphingomyelin levels disrupt the cutaneous barrier, triggering an inflammatory

cascade both with immune cell activation and cytokine release (eg, tumor necrosis factor-alpha

(TNF-α). (57)

Several genes involved in sphingolipid synthesis and function have been demonstrated to exhibit

aberrant expression in HS. Ceramide synthase-2 (CerS2) and Sphingosine kinase-2 (SPHK2)

expression are significantly downregulated in HS when compared with unaffected skin. CerS2

may be involved in cell growth regulation, whereas SPHK2

encodes for a sphingosine kinase that accelerates the phosphorylation of sphingosine into its

active form, sphingosine 1-phosphate, which in turn moderates cellular homeostasis, promotes

angiogenesis and, possibly, carcinogenesis. (58) Other products of the sphingolipid pathway that

are elevated in lesional HS include galactosylceramides and gangliosides. Galactosylceramide

activates natural killer cells and promotes inflammation. (58)

Aberrant Keratinocyte Barrier Function. Hotz et al have shown that keratinocytes derived from

the hair follicles of HS patients may be intrinsically prone to inflammation and

aberrant production of interferon gamma-induced protein-10 (IP-10) and chemokine (C-C motif)

ligand-5 (CCL5) in the absence of known inflammasome mutation. (59)

This is thought to contribute to subclinical inflammation, follicular plugging, and cyst formation.

Several rare conditions involving abnormalities in epidermal proteins and function have been

reported to be associated with HS, though the causal link is not as well documented. Rare

associations with HS include nevus comedonicus syndrome, keratitis ichthyosis deafness

syndrome, pachyonychia congenita types 1 and 2, and Dent 2 disease. (60-67) The etiological

26

relationship between HS and these syndromes is yet to be determined, though these findings

offer an intriguing avenue for future investigation.

Genes Involved in Inflammation

Antimicrobial Proteins (AMPs). When the epidermal barrier is breached, AMP activity increases

to provide protection from pathogens. The AMP family consists of human β-defensin-1

(hBD1), hBD2, hBD3 and S100 proteins S100A7 (psoriasin), S100A8 (calgranulin A), and

S100A9 (calgranulin B) produced by keratinocytes. They are important in protection against

foreign bacteria. AMPs may have a dual role in HS:Decreased AMP activity favors bacterial

overgrowth and biofilm formation, whereas AMP overexpression stimulates innate immunity

and worsens inflammation. Specifically, one theory regarding the pathogenesis of HS involves

bacteria’s ability to continue growing within a closed, damaged hair follicle. In support of this

theory, levels of hBD1, hBD3, and S100A7 in HS have been shown to be less than in psoriasis

and atopic dermatitis. (68) In a different study, however, comparing lesional vs nonlesional skin

of 17 HS patients, a number of keratinocyte derived AMPs (eg, hBD-2, LL-37 [cathelicidin] and

matrix HS and has been proposed as a serum biomarker for HS. (72,73)

metalloproteinase-1 [MMP1]) were found to be significantly increased in HS lesions. The

authors reported that high level of AMPs can generate inflammatory reaction in HS patients. (69)

Although protective against bacterial and dermatophyte infections, genetic overexpression of

these peptides contributes toward the inflammatory state of HS. (70) However, paradoxically,

despite predisposing patients to HS, the degree of AMP overexpression (eg, hBD-3 and RNase-

7) inversely correlates with disease severity, illustrating the complexity of innate immunity and

27

microbiota interaction. (71) Another protein with AMP properties, S100A8/A9 (calprotectin),

has gained popularity as a fecal biomarker in inflammatory bowel disease. It is upregulated in the

skin and blood of patients with HS and has been proposed as a serum marker. (72, 73)

S100A8/A9 contributes to inflammation by recruiting macrophages and neutrophils to the skin.

(59) Similarly, Toll-like receptor 2 (TLR2), whose role is to recognize pathogen associated

molecular patterns, is highly expressed by dendritic cells and macrophages, indicating that

stimulation of inflammatory cells by TLR2-activating microbial substances may be an important

trigger for chronic inflammation seen in HS. (74-76)

Cytokines and Chemokines. The IL-12/IL-23 pathway may be important in the pathogenesis of

HS.77 IL-23 is vital for the development of Th17 cells producing IL-17. Both IL-17 and IL-23

are upregulated in HS lesions. (78) Haplotype h2 of the interleukin 12 receptor β1 (IL-12Rβ1)

seems to have a significant impact on the severity of HS: Patients carrying this haplotype have an

almost 3-fold greater risk for the development of severe HS. (77) Conversely, single-nucleotide

polymorphisms at the promoter region of the TNF-α gene increase gene expression and

production of TNF-α, leading to higher rates of disease susceptibility, while paradoxically

correlating with a better response to anti–TNF-α treatments. (79) Smoking and obesity cause

Th17/Treg imbalance by increasing IL-17 levels that lead to inflammation in HS patients. (80)

Conclusion

HS patients frequently report a positive family history, strongly suggesting a genetic component

to this disease. We provide a summary of reported genetic mutations documented in familial HS

cases (Table 1) and discuss the reported evidence for polygenic modes of presentation. HS is

28

inherited as a monogenic trait in less than 7% of patients, in whom it is attributed to

abnormalities both in Notch and inflammasome signaling pathways. Patients with inherited. HS

due to Notch signaling defects often have both a positive family history and a more severe

phenotype. Cases due to PSTPIP1 or related gene mutations may present with severe HS and

autoinflammatory syndromes. The risk of developing HS may be increased by the inheritance of

mutations/ alterations in genes involved in epidermal proliferation, function, and homeostasis.

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2011;65(4):790-798. doi:10.1016/j.jaad.2010.07.010.

79. Savva A, Kanni T, Damoraki G, et al. Impact of Toll-like receptor-4 and tumour necrosis factor

gene polymorphisms in patients with hidradenitis suppurativa. Br J Dermatol. 2013;168(2):311-

317. doi:10.1111/bjd.12105.

80. Melnik BC, John SM, Chen W, Plewig G. T helper 17 cell/ regulatory T-cell imbalance in

hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and

autoimmune comorbidities. Br J Dermatol. 2018;179(2):260- 272. doi:10.1111/bjd.16561.

Figure 1. Hidradenitis suppurativa can be inherited as a polygenic or monogenic trait.

FGFR2: fibroblast growth factor-receptor 2 gene, NCSTN: nicastrin, OCRL1: Inositol

polyphosphate 5-phosphatase, POFUT1: Protein O-Fucosyl Transferase 1, PSEN: presenilin,

PSENEN: presenilin enhancer, gamma-secretase subunit, SERCA: sarcoendoplasmic reticulum

calcium adenosine triphosphatase, Keratins 6A and 17 LPIN2: Lipin 2, MEFV: Mediterranean

Fever NLRP3: nucleotide-binding domain leucine-rich repeat containing protein 3, NLRP12:

34

nucleotide-binding domain leucine-rich repeat containing protein 12, NOD2 and PSTPIP1:

Proline-Serine-Threonine-Phosphatase-Interactive Protein 1. CerS2: Ceramide synthase 2 and

SPHK2: Sphingosine kinase 2 IP-10: interferon gamma-induced protein 10, CCL5: chemokine (C-

C motif) ligand 5 MMP1: matrix metalloproteinase 1, S100A7, hBD: human β-defensin 1,2,3

Figure 2. Hidradenitis suppurativa genes are involved in: A.) Notch signaling pathway. Mutations

in any of the following four genes result in the downregulation of this pathway: Presenilin

Enhancer (PSENEN); Nicastrin (NCSTN); Protein O-fructosyltransferase 1 (POFUT1); the amyloid

precursor protein (APP). B.) Autoinflammatory disorders (AID). In cryopyrin-associated periodic

syndromes (CAPS), mutation in NLRP3 (nucleotide-binding domain and leucine-rich repeat

35

containing protein 3) results in increased assembly of NLRP3 inflammasome and active caspase-

1 through interaction with ASC and procaspase 1. In PAPA (Pyogenic Arthritis, Pyoderma

gangrenosum, and Acne) and PASH (Pyogenic Arthritis, Pyoderma gangrenosum, Acne,

Suppurative Hidradenitis), mutation in PSTPIP1(proline-serine-threonine-phosphatase-

interactive protein 1) lead to a prolonged binding of PSTPIP1 to pyrin via the SH3 domain which

leads to impaired pyrin function and results in constitutive activation of NLRP3, production of IL

(Interleukin)1β and inflammation. In FMF (Familial Mediterranean Fever), MEFV (Mediterranean

Fever) gene mutation in pyrin results in caspase-1 activation. Active caspase 1 cleaves pro-IL-1β

into its active form, IL-1β. Nucleotide-binding oligomerization domain-containing protein 2

(NOD2) activates nuclear factor-kappa B (NF-κB) that translocate into the nucleus and drives the

transcription and production of Pro-IL1β and other inflammatory cytokines.

Mutation Exon Mutation type

Reported disease Ethnic origin

Familial sporadic

Sample Study design

Reference

PSENEN c.194T>G

NR Missense Dowling Degos Disease (DDD)

Chinese Familial Blood

Case series

(84)

PSENEN c.167-2A>G

NR Splice site Dowling Degos Disease (DDD)

Chinese Familial Blood

Case series

(84)

PSENEN c.168T>G

NR Transversion Dowling Degos Disease (DDD)

Jewish Ashkenazi

Familial Blood/saliva Case series

(85)

POFUT1 c.430-1G>A

Exon 4

Splice site Dowling Degos Disease (DDD)

NR Sporadic Blood Case report

(86)

36

Connexin 26

A40V

NR Point keratitis-ichthyosis-deafness (KID) syndrome

White Sporadic Blood Case report

(87)

FGFR2 c.G492C, p.K164N

Exon 5

Missense Nevus Comedonicus Syndrome (NCS)

NR Sporadic Blood Case report

(88)

Keratin K6a 1390A>C

Exon 7

Missense Pachyonychia congenita (PC)

NR Sporadic Blood Case report

(89)

OCRL1 c.952C>T c.1477C>T c.1567G>A

Exon 11 & 15

NR Dent disease 2 NR Sporadic Blood Case series of 4 patients

(90)

*Chromosome 21

__ Trisomy Down syndrome NR Sporadic Blood Case series of 5 patients

(91)

MEFV M680I and V726A

Exon 10

Compound heterozygous

Familial Mediterranean Fever (FMF)

Turkish Sporadic Blood Case study

(92)

PSTPIP1 c.831G>T (p.E277D)

Exons

10 &

11

Missense Pyogenic Arthritis,

Pyoderma

Gangrenosum, Acne,

and Hidradenitis

Suppurativa

(PAPASH)

Moldavian

Sporadic Blood Case report

(93)

PSTPIP1 c.1034A>G

Exon

15

Missense Pyoderma

Gangrenosum, Acne,

and Hidradenitis

Suppurativa (PASH)

Japanese Familial Blood Case report

(94)

NCSTN c.344_351del; NM_015331.2)

Exon

4

Frameshift Pyoderma

Gangrenosum, Acne,

and Hidradenitis

Suppurativa (PASH)

NR Familial (95)

Table 1. Reported mutations in syndromic HS and associated diseases.

37

FGFR2: Fibroblast Growth Factor-Receptor 2, MEFV: Mediterranean Fever, NCSTN: Nicastrin,

NR: not reported, OCRL1: Inositol polyphosphate 5-phosphatase, POFUT1: Protein O-Fucosyl

Transferase 1, PSENEN: presenilin enhancer, gamma-secretase subunit, PSTPIP1: Proline-

Serine-Threonine-Phosphatase-Interactive Protein 1. *not a mutation.

After understanding the genetic aspect of HS pathogenesis and the relation between

autoinflammatory genes and HS. We decided to run genetic testing using the autoinflammatory

gene panel in any patient with positive family history of HS in more than 1 degree relative.

38

III. Novel Variants of MEFV and NOD2 Genes in

Familial Hidradenitis Suppurativa

Abdulhadi Jfri1, Elizabeth O'Brien1, Ivan Litvinov1, Elena Netchiporouk1

1Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Rm. L8-

201, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada

Keywords: Hidradenitis, hidradenitis suppurativa (HS), familial hidradenitis suppurativa, familial

Mediterranean fever (FMF), genetics, autoinflammatory gene panel.

Abstract

We report a two-generation Canadian family of Armenian ancestry with hidradenitis suppurativa

(HS) where novel mutations in MEVF and NOD2 genes were identified. The father and both

children shared a mild-moderate HS phenotype together with features of follicular occlusion (e.g.

acne, folliculitis). We recommend genetic testing with a periodic fever/autoinflammatory

disorder panel in patients with a strong family history of HS and lack of common triggers such as

smoking and obesity.

Introduction

39

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by persistent

or recurrent flares of inflamed painful nodules, sinuses and scars in the axilla, groin, or both. (1)

Its prevalence ranges between 0.1% - 4% worldwide. (2) Smoking, metabolic syndrome and

Crohn’s are frequent comorbidities in HS patients. (3) The pathophysiology of HS is not fully

understood. It is thought to be related to follicular occlusion resulting from infundibular keratosis

and hyperplasia. Eventually the hair follicle ruptures, followed by a massive local immune

response resulting in painful inflammation, abscess formation, and in later stages, sinus tract

formation and scarring. (4, 5)

HS is a multifactorial disease where genetic factors account for up to 30-40% of disease

susceptibility. Genes reported to be associated with heightened risk of developing HS include those

with critical role in innate immunity such as inflammasome activation (e.g. Mediterranean fever

gene (MEFV)and Nucleotide-binding oligomerization domain-containing protein 2 (NOD2)). (6)

We report here a two-generation Canadian family of Armenian ancestry with HS in which novel

mutations of MEVF and NOD2 genes were identified. The father and both children shared a mild-

moderate HS phenotype together with features of follicular occlusion (e.g. acne, folliculitis).

Case report

An Armenian-Canadian family, including three members with HS, was evaluated in our clinic.

The 66-year-old father was known for HS Hurley stage II for 3 years, as well as psoriasis and

asthma. His HS was well controlled on oral doxycycline with Physician Global Assessment (HS-

PGA) of 1; pain visual acuity scale (VAS) in the past week of 1. He is an ex-smoker with a 30-

pack- year smoking history and has a body mass index (BMI) within normal range. On physical

examination, he was noted to have numerous follicular pustules, double-headed open

comedones, and scars from previous lesions on theback and axillae (Figure 1.A).

40

The 22-year-old son developed HS Hurley stage II at 19 years of age. Otherwise he was known

for asthma and folliculitis necrotica. He never smoked and has a normal BMI. His disease was

partially controlled with oral doxycycline, daily triclosan washes as well as intermittent

intralesional triamcinolone (5mg/ml) injections to control disease flares. He had an HS-PGA of 3

and pain VAS of 6. On examination, he had multiple follicular pustules on the scalp and trunk,

tender inflammatory nodules in the axillae and bilateral inner thighs. (Figure 2. B)

The 20-year-old daughter, also a non-smoker with normal BMI, presented with severe acne,

alopecia areata, scarring folliculitis and HS Hurley stage I for the past 2 years. She was well

controlled with ND-YAG laser purposed for hair removal and triclosan antiseptic washes.

She had multiple follicular pustules on the back and thighs and double-head comedones in the

groin. (Figure 3. C).

Given the co-occurrence of HS in 3 immediate family members and lack of usual risk factors,

genetic testing for HS panel was offered. All three submitted sera for RNA sequencing using the

genetic panel for periodic fever/autoinflammatory disorders that included 23 genes commercially

available (Fulgent genetics, California) with 3 additional genes: PSEN1, PSENEN, and NCSTN.

The results showed that the father had the following mutations: MEFV gene NM_000243.2

autosomal recessive (c.2177T>C), NOD2 gene NM_022162.2 autosomal dominant (c.2923C)

and PLCG2 (phospholipase C gamma 2) autosomal dominant gene NM_002661.4 (c.2948C>T).

The son had NOD2 autosomal dominant (c.2923C) mutation, while the daughter had MEFV

autosomal recessive (c.2177T>C). Neither the patients nor their relatives had any clinical signs

or symptoms suspicious for Familial Mediterranean fever.

Discussion

41

While numerous HS classifications schemes were proposed, one of particular interest relates to

disease phenotype based on the predominate morphology of lesions and their locations. The

follicular phenotype is characterized by pustules, double-headed comedones and cerebriform

scars and often clusters in families. (7) The other clinical subtypes include inflammatory and

mixed. Genotype–phenotype study was done previously but failed to identify any correlation. (8)

The MEFV gene encodes for pyrin, the essential protein for inflammasome function. While the

inflammasome’s normal function is defense against pathogens, overstimulation of its pathway can

cause multisystem autoinflammatory disorders such as Familial Mediterranean Fever (FMF). Our

patient’s variant of MEFV gene has been reported in patients with FMF, but not previously in HS.

The coexistence of HS with FMF was described in two unrelated Turkish patients, both of whom

had M694V/V726A MEFV gene mutations with severe HS Hurley stage III, with one having severe

acne conglobata. (9) Similar to the family in our case report, all affected members of those families

have the follicular type of HS with numerous comedones.

In a cohort of 151 patients with confirmed FMF where all patients were clinically screened for HS,

6 patients were found to have HS and reviewing their MEFV gene mutations showed

M694V/M694V, V726A/V726A, M694V/M694V, V726A/F479L/E148Q, M694V/−, and one

was not done. (10) This report did not discuss the phenotype of patients nor their HS severity. In

addition, FMF was found in 13 (0.7%) out of 4417 patients with HS in a cross-sectional study in

which HS was significantly associated with an odds ratio (OR) of 11.1 and 95% confidence interval

(CI) of 6.0-20.4. (11)

NOD2 gene encodes for NOD2 protein, also known as caspase recruitment domain-containing

protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), and is another important

42

component of inflammasome function through recognition of bacterial peptidoglycans. (6)

Autosomal dominant mutation in NOD2 has been associated with Blau syndrome, increased risk

of psoriatic arthritis, and increased susceptibility for inflammatory bowel diseases (IBD)

(ulcerative colitis and Crohn’s). (12) There is a significant association between IBD and HS,

Crohn’s disease with pooled OR of 2.12 and 95% CI (1.46-3.08) and ulcerative colitis with pooled

OR, 1.51 and 95% CI (1.25-1.82). (13) To date, the variant of NOD2 gene reported in our family

has not been reported previously in HS or any of the previously mentioned conditions.

PLCG2 encodes for PLCG2 enzyme which is critical for B cells, natural killer cells and mast

cells in recognizing and fighting bacterial and viral infections. Mutation in PLCG2 has been

associated with PLCG2-associated antibody deficiency and immune dysregulation (PLAID)

wherein patients develop cold urticaria, autoimmunity, and recurrent cutaneous bacterial

infections. (14) The PLCG2 mutation has not previously been reported in HS. Therefore, the

significance of this mutation in our patient is unknown.

It is extremely interesting that the father has 3 mutations with HS-causing potential, all of which

are found on chromosome 16 (FMF gene 16p13.3, NOD2 16q12.1 and PLCG2 16q23.3).

Conclusion

This is the first report of familial HS involving mutations in NOD2 and MEFV in an Armenian-

Canadian family. Their phenotype was predominantly follicular and mild. We recommend

genetic testing with a periodic fever/autoinflammatory disorders gene panel in patients with a

strong family history of HS with either a severe clinical phenotype or the lack of common

43

triggers such as smoking and obesity. The notable occurrence of three separate mutations

affecting chromosome 16 warrants further study.

References

1. Jfri A, O'Brien E, Alavi A, Goldberg SR. Association of hidradenitis suppurativa and

keloid formation: A therapeutic challenge. JAAD Case Rep. 2019;5(8):675-8.

2. Jemec GB, Kimball AB. Hidradenitis suppurativa: Epidemiology and scope of the

problem. J Am Acad Dermatol. 2015;73(5 Suppl 1):S4-7.

3. Miller IM, McAndrew RJ, Hamzavi I. Prevalence, Risk Factors, and Comorbidities of

Hidradenitis Suppurativa. Dermatol Clin. 2016;34(1):7-16.

4. Jemec GB, Hansen U. Histology of hidradenitis suppurativa. J Am Acad Dermatol.

1996;34(6):994-9.

5. von Laffert M, Stadie V, Wohlrab J, Marsch WC. Hidradenitis suppurativa/acne inversa:

bilocated epithelial hyperplasia with very different sequelae. Br J Dermatol. 2011;164(2):367-71.

6. Jfri AH, O'Brien EA, Litvinov IV, Alavi A, Netchiporouk E. Hidradenitis Suppurativa:

Comprehensive Review of Predisposing Genetic Mutations and Changes. J Cutan Med Surg.

2019;23(5):519-27.

7. Martorell A, Jfri A, Koster SBL, Gomez-Palencia P, Solera M, Alfaro-Rubio A, et al.

Defining Hidradenitis Suppurativa Phenotypes Based on the Elementary Lesion Pattern: Results

of a Prospective Study. J Eur Acad Dermatol Venereol. 2020.

8. Frew JW, Hawkes JE, Sullivan-Whalen M, Gilleaudeau P, Krueger JG. Inter-rater

reliability of phenotypes and exploratory genotype-phenotype analysis in inherited hidradenitis

suppurativa. Br J Dermatol. 2019;181(3):566-71.

9. Vural S, Gundogdu M, Kundakci N, Ruzicka T. Familial Mediterranean fever patients

with hidradenitis suppurativa. Int J Dermatol. 2017;56(6):660-3.

10. Abbara S, Georgin-Lavialle S, Stankovic Stojanovic K, Bachmeyer C, Senet P, Buob D,

et al. Association of hidradenitis suppurativa and familial Mediterranean fever: A case series of 6

patients. Joint Bone Spine. 2017;84(2):159-62.

11. Hodak E, Atzmony L, Pavlovsky L, Comaneshter D, Cohen AD. Hidradenitis

Suppurativa Is Associated with Familial Mediterranean Fever-A Population-Based Study. J

Invest Dermatol. 2017;137(9):2019-21.

12. Yao Q. Nucleotide-binding oligomerization domain containing 2: structure, function, and

diseases. Semin Arthritis Rheum. 2013;43(1):125-30.

13. Chen WT, Chi CC. Association of Hidradenitis Suppurativa With Inflammatory Bowel

Disease: A Systematic Review and Meta-analysis. JAMA Dermatol. 2019.

14. Milner JD. PLAID: a Syndrome of Complex Patterns of Disease and Unique Phenotypes.

J Clin Immunol. 2015;35(6):527-30.

44

During our recruitment of HS patients, we observed a major impact of their quality of life that

vary based on their clinical severity. So, in the next chapter we decided to study the association

between those psychosocial impact scores and the clinical severity measures.

45

IV. Psychosocial Impact of Clinical Severity on

Hidradenitis Suppurativa

Abdulhadi Jfri1, Elizabeth O’Brien1, Ivan Litvinov1, Elena Netchiporouk1

1Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Rm. L8-

201, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada

Keywords: Hidradenitis, hidradenitis suppurativa, quality of life, depression, psychosocial

impact

Abstract

Background

Hidradenitis suppurativa (HS) places a significant burden on patients’ quality of life (QoL).

Objective

To assess Hidradenitis suppurativa (HS) patients’ Quality of Life and mental health using

Dermatology Quality of Life Index and Beck Depression Inventory and correlate findings with

demographics/disease severity.

Methods

Single center cross-sectional survey conducted from 10/2018-12/2019. Eligibility ≥18 years,

clinical visit for HS patients with no prior diagnosis of depression/mental health disorder. Survey

included 2 questionnaires. HS clinical severity was assessed using Hurley staging, pain visual

46

analogue scale in the last week, HS physician global assessment, International HS severity

scoring system (IHS4) and severity assessment of HS.

Results

131 patients were included. Results showed large effect on patient’s life (38, 29%) and mild

mood disturbance (27,21%), with 36 patients (27%) showed probable major depressive disorder

(MDD) correlated most with IHS4, and statistically significant (p<0.001) correlation between

Dermatology Quality of Life Index and pain score in last week.

Limitations

Single center design and lack of control group.

Conclusion

Depression prevalence from 19-27% in HS patients with unknown depression, with effect on life

correlated to pain in the last week.

Introduction

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by persistent

or recurrent flares of inflamed painful nodules, sinuses and scars in the axilla, groin or both. (1,

2) Its prevalence ranges between 0.1% - 4% worldwide. (3, 4) HS tends to affect females 3-times

more than males. (5, 6) Disease usually starts after puberty, early in the third decade of life.

Prepubertal onset is rare and is associated with positive family history and more severe

phenotype. (7) Genetics can play a role in the pathogenesis of HS with approximately 30% report

family history. (8). Clinically, HS can present with follicular, inflammatory or mixed phenotype.

(9).The diagnosis of HS takes on average 7 years. (10) Smoking and obesity are common

associations in HS patients along with hypertension, diabetes, thyroid dysfunction, Crohn’s

disease and polycystic ovarian syndrome (PCOS). (11-14) Over the years, several clinical

47

parameters have been found associated with a worse disease activity including male sex, younger

age at disease onset, obesity, smoking, and areas of involvement localized to axilla, perianal and

mammary folds. (12) Pain affects up to 97% of patients, (15-17) and is significantly worse

compared to psoriasis. (18)

HS has a great impact on the patient’s quality of life. It was found that HS has a great emotional

impact on patients and promotes isolation due to fear of stigmatization. (19) Patients report

embarrassment, self-consciousness, and inability to participate in social and athletic activities.

(20) The foul odour of the HS lesions can be very embarrassing and often lead to social

withdrawal and isolation. (21, 22) Higher Hurley staging, anogenital localization, pain severity

and high BMI (>25) were the most important factors affecting the quality of in patients with HS

(23-25) Investigating patient’s sexual health, Kurek et al. found that patients with HS have a

significantly higher impairment of sexual health compared to age-, sex- and body mass index-

matched controls. (26) The prevalence of depression among patients with HS ranges between 6 -

43% which is higher than general population. (18, 25, 27-30)

In a cohort of 153 patients, 33% patients met the criteria for diagnosing major depressive

disorder (MDD). (31) Patients with HS have major body image impairment, which might lead to

depression. (32) The emotional and the psychological impact of HS on patients have led to the

increased risk of opioid, cannabinoids and alcohol abuses. (33) Up to date, one study of 26 HS

patients assessed for depressive symptoms using beck depression index-21 (BDI-21). (34)This

study was limited by the small sample size and lack of correlation with HS clinical severity

measures. Here, we present a large prospective cohort of 131 HS patients where we assessed the

48

psychosocial status using BDI-21 and dermatology quality of life index (DLQI). Furthermore,

we correlated these outcomes with the most widely used HS clinical severity assessment tools.

Material and methods

Patients

This study was approved by the McGill University Health Center (MUHC) research ethics board

(REB-5282). The ethical principles of the Declaration of Helsinki (1964) and subsequent

amendments and applicable regulatory requirements were followed. This study was conducted at

the Dermatology Department of the Montreal General Hospital from October 2018 until December

2019. Adult patients attending the HS clinic were offered to participate in the study if they met the

inclusion criteria of age above 18 years, read and write in English or French. All recruited patients

underwent history and physical examination, disease activity scoring systems and 2 patient-centric

questionnaires on depression and quality of life (DLQI and BDI-21).

Assessment of disease severity

Detailed history was taken from patients that included age, gender, ethnicity, year of HS symptoms

and year of HS diagnosis, first degree family history of HS, past medical, past surgical, smoking

history, flares in the past 4 weeks, missed work days in the past 4 weeks due to HS (absenteeism),

bothered work days due to HS in the past 4 weeks (presenteeism). Patients were examined

clinically and assessed for body mass index (BMI), area affected and clinical disease severity using

validated score such as the Hurley staging, hidradenitis suppurativa physician global assessment

(HS-PGA), The Severity Assessment of Hidradenitis Suppurativa (SAHS) and International HS

severity scoring system (IHS4).

49

Hurley stages (0-3) assess locoregional disease severity and are defined as mild (1) if no sinus tract

or scarring is seen, moderate (2) when 1 or few sinuses are seen and severe (3) when disease in

confluent and characterized by interconnected sinuses and scars. The HS-PGA has 6 categories

that range from clear (0 lesions) to very severe (over 5 abscesses or draining fistulas). This system

is based on the number of abscesses, draining fistulas, inflammatory and non-inflammatory

nodules, however it does not consider the number of body regions involved. This scoring system

is very useful in observing the progression of the inflammation. (35)

The SAHS score is a staging system that combines three physician-rated items with two patient-

reported items. The three physician-rated items were included: number of involved regions,

number of inflammatory and/or painful lesions other than fistula (ILOF), and number of fistulas.

The 2 patient-reported items were: number of new boils or number of existing boils which flared

up during the past 4 weeks and the current severity of pain of the most symptomatic lesion in the

course of their daily activities (e. g, sitting, moving, or working) on a numerical rating scale (NRS-

11) ranging from 0 to 10. SAHS score of ≤ 4 is mild, 5 – 8 moderate, and severe disease ≥ 9. The

SAHS score is not based on the identification of different inflammatory HS lesions (e.g.,

inflammatory nodule vs abscess) because such a differentiation can present a challenge in daily

clinical routine for some patients with HS, and its clinical impact is questionable. Thus, the SAHS

score simply differentiates be- tween ILOF and fistula. (36) Since HS is a painful condition, the

visual analogue scale (VAS) for pain was used to grade the intensity of the pain objectively on a

unidimensional scale from 0-10. (37) Since anemia is more prevalent in HS, (38) hemoglobin level

was measured if no recent test within 6 months period.

50

Assessment of quality of life and psychological impact

DLQI is a useful tool that has been used since 1994 to assess the effect of a dermatology

disorder, including HS, on the patient’s QoL. It is a 10-item questionnaire that rates disease

impact from 0 (i.e., no effect on the patient’s life) to 30 (the disease has an extremely large

impact on the patient’s life) with 2-5 indicating small impact, 6-10 moderate impact and 11-20

severe impact. (39)

BDI-21 is one of the most commonly used tools to assess and grade depression. (40). A score up

to 10 is considered normal, 11-16 indicates mild mood disturbance, 17-20 borderline clinical

depression. 21-30 moderate, 31-20 severe, and over 40 indicates extremely severe depression.

BDI-21 maximum score is 63. However, there is no approved cut off for diagnosing depression,

because cut off varies based on the population and the sittings (in-patient vs out-patient). For

example, the optimal BDI-21 cut off in post-myocardial infarction patients to diagnose major

depressive disorder (MDD) was ≥ 16. (41) Another proposed cut off to diagnose MDD in

comparison to DSM-IV was ≥ 21 in out-patients with chronic pain. (42) In psoriatic patients a

cut off 17 was used suggest MDD and necessitate a referral to psychiatry. (43)

Statistical analyses

Descriptive statistics were used for demographic data (median and IQR for non-normally

distributed data, frequencies and percentages for categorical data). The Spearman’s Rank

Correlation Coefficient was used to examine potential associations between BDI-21 score and

DLQI score with: age, delay in HS diagnosis, BMI, VAS, PGA, IHS4, SAHS, missed work days

in the past 4 weeks, bothered work days in the past 4 weeks. The Fisher’s Exact Test was used to

examine potential associations between BDI-21 severity categories and DLQI severity

51

categories. Ordinal Logistic Regression analyses were used to evaluate all variables for potential

predictive value on BDI-21 and DLQI severity categories, with verification of proportional odds

assumption in Ordinal Logistic Regression. Odds Ratio’s (OR) with corresponding 95%

confidence intervals (CI) were provided for significant results. All analyses were conducted

using STATA® (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX:

StataCorp LLC.) and unless otherwise noted were interpreted with a Type I Error Rate of alpha =

0.05 level of significance.

Results

A total of 131 adult HS patients were included in the study. Patient’s demographics are

summarized in Table. I. The majority were females 76 (58.02%) and the most frequent ethnicity

was Caucasian 82 (62.6%) with a mean (SD) age of 38.11 (±14.32). A first-degree family history

of HS was reported in 34 (25.95%). A history of smoking was reported in 77 patients: there

were 57 active smokers 57 (43.51%), 20 ex-smokers (15.27%) and 54 patients who had never

smoked (41.22%). The most common associated medical condition was diabetes mellitus type 2

(n=16; 12.21%). The most reported dermatological comorbidity was acne vulgaris in 20

(15.26%) followed by psoriasis with a total of 11 (8.40%) of whom 9 had psoriasis vulgaris and

2 had anti-TNF induced psoriasis (Table. II).

Clinical severity of HS scores is summarized in Table III. Patients were classified as Hurley I-

mild (n=39; 29.77%), Hurley II-moderate (n=47; 35.88%), or Hurley III -severe (n=45; 34.35%).

SAHS score was mild in 46 patients (35.11%), moderate in 48 (36.64%) and severe in 37

(28.24%). Most patients (n=118; 90.01%) reported presence of pain related to HS on the pain

VAS in the last week. The majority [52 (39.69%)] had moderate pain (4-6 out of 10). The mean

52

(SD) IHS4 was 7.21 “moderate disease” (±7.01). Anemia defined as hemoglobin <120g/dl for

females and <130g/dl males was prevalent in 31 patients (23.66%). Among the 131, 102 patients

were currently employed with 45 (43.27%) reporting absenteeism and 79 (76.7%) reporting

presenteeism that was either physically or emotionally related to HS.

Most patients [107 (81.68%)] were on combined systemic and topical treatment during the 4

weeks prior to the study with 21 patients (16.03%) on biologic therapy. A history of past surgical

intervention for HS (incision & drainage, deroofing or complete lesional excision) was reported

by 47 (35.88%). (Table. I)

HS and quality of life

Per the DLQI results, HS impacted the quality of life of 118 (90.01%) subjects, with reported

impact ranging from small (21, 16.03%) or moderate (29, 22.14%) to large (38, 29.01%) or

extreme (30, 22.90%). Spearman’s correlation coefficient for DLQI showed statistically

significant correlation rho (p-value) between DLQI and pain VAS score 0.54 (p<0.001), PGA

0.33 (p<0.001), IHS4 0.55 (p<0.001), SAHS 0.45 (p<0.001). Age, delayed diagnosis, BMI,

absenteeism and presenteeism were not statistically significant. (Table IV) Worse QoL as

measured by the DLQI was significantly associated with more depressive symptoms (higher

BDI-21) (Fisher’s Exact Test: p = 0.01).

Univariate Ordinal Logistic Regression analyses showed multiple statistically significant

predictors with OR (95% CI) for the DLQI severity (proportional odds assumption satisfied for

each). These included pain VAS score (<0.001) 1.5 (1.3-1.7), PGA (<0.001) 1.5 (1.2-1.9), IHS4

(<0.001) 1.2 (1.1-1.2), SAHS (<0.001) 1.3 (1.2-1.5).

53

HS and Depression

BDI-21 score was relevant (>10) indicating the presence of depressive symptoms in 63 patients

with the following severity: 27 mild (20.61%), 11 borderline (8.4%), 15 moderates (11.45%), 8

severe (6.11%), and 2 extreme depression (1.53%). Considering a BDI-21 cut-off score for

probable MDD of ≥ 21 or >17, these results would translate into (25) 19% and (36) 27%,

retrospectively HS patients having a probable diagnosis of MDD and necessitating further

psychologic assessment and treatment. Spearman’s correlation coefficient was statistically

significant for BDI-21 and showed that more worse depression was associated with higher DLQI

score (p<0.001), pain VAS score (p=0.009), PGA (p=0.024), IHS4 (P<0.001), SAHS (P<0.001),

absenteeism (p=0.009) and presenteeism (p=0.006). Age, delay in HS diagnosis, BMI were not

statistically significant (p > 0.05 for each). (Table IV)

Univariate Ordinal Logistic Regression analyses showed multiple statistically significant

predictors with OR (95% CI) for the BDI-21 severity (proportional odds assumption satisfied for

each). These included PGA (p-value=0.037) 1.3 (1.0-1.6), IHS4 (p<0.001) 1.1(1.0-1.1), SAHS

(p=0.001) 1.2 (1.1-1,3). This means for example, for each one level increase in PGA

(0/1/2/3/4/5), the odds of the highest category of BDI-21 vs the combined lower categories are

approximately 1.3 times greater.

Discussion

HS greatly impacts the psychological wellbeing of the patients. Up to this point, only one small

study assessed depression using BDI-21 of 26 HS patients and showed a mean (SD) total BDI-21

score of around 10.69 “mild depression” ± (10.13) and mean (SD) DLQI score of 8.31 “moderate

impact” ± (7.39), with women having higher BDI-21 and DLQI scores than men. They found

54

that a higher Hurley stage at visit (p = 0.001), female gender (p = 0.018), and higher BDI-21

total score (p = 0.022) were variables that were significantly affected by the total DLQI score in

stepwise regression analysis. (34) However, in this published study with a small sample size,

most patients had mild-moderate disease and only 2 had severe (Hurley stage III).

Similarly, we found in our study that higher BDI-21 scores were significantly associated with

higher DLQI scores. In the current study, the BDI-21 score was also in the “mild depression”

category by 12.33 ± (10.27) but we found a mean (SD) DLQI of 12.25 “large impact” ± (8.50).

Women had more depressive symptoms than men with (BDI-21 more than 10). However, among

the 10 (7.63%) severely depressed patients (BDI-21 score ≥ 31-40), 6 (60%) were men including

the two who had extreme depression (BDI-21 score >40.

Among other chronic inflammatory skin condition, in one study of psoriasis, a BDI-21 score of

above 17 was interpreted as indicating the presence of possible depression an indication to refer

to psychiatry. A total of 67% out of 100 psoriatic patients were found to be depressed and were

eventually referred to psychiatry. (43) In our study if we considered the same criteria to

diagnose depression in patients with unknown mental disorder, 36 patients (27.48%) with a BDI-

21 score of above 17 would be considered having probably MDD. This necessitate the

importance of screening HS patients for depressive symptoms and consider referral to

psychiatry.

Multiple studies have looked at the impact of HS on patient’s lives. One prospective case series

studied 55 HS patients’ quality of life and showed a mean (SD) DLQI score of 10 ± (8.8),

indicating a moderate effect on patients' lives. Hurley stage and clinical count of the lesions have

55

been significantly correlated with DLQI score. (44) Another study of 211 HS patients and 233

dermatological controls showed significantly higher DLQI for HS cases compared to controls

with mean (SD) DLQI score of 8.4 “moderate impact” ± (7.5) vs. 4.3 “small impact” ± (5.6) (P <

0.0001), respectively, and high DLQI severity correlated with Hurley stage severity scores (18).

In addition, a report of 94 HS patients, showed a DLQI mean (SD) score of 11.43± (6.61) which

represent a large effect on patients' lives, with female patients having more severe quality of life

impairment (12.94 ±7.24) compared to male patients (9.63 ± 5.31, p = 0.01). (17) In the current

study, the overall mean (SD) DLQI score was similar, at 12.25 ± (8.50),

Conclusion

HS impacts the quality of patients’ lives and may lead to depressive symptoms. Depression is

likely underdiagnosed in patients suffering from HS. The severity of the depression based on

BDI-21 correlated the most with IHS4 which can be used to catch high risk patients that require

screening for depression. The degree of HS impact on patient’s quality of life represented by

DLQI correlates the most with pain measured on VAS in the past week which can be clinically

used to anticipate the degree of impact on DLQI in HS patients.

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patients with hidradenitis suppurativa: a Canadian study. Am J Clin Dermatol. 2015;16(1):61-5.

Total 131, no. (%)

Sex

Females 76 (58.02)

Males 55 (41.98)

Ethnicity

African 17 (12.98)

Caucasian 82 (62.6)

Middle Eastern 10 (7.63)

Native Canadian 8 (6.11)

Asian 7 (5.34)

Latino 7 (5.34)

BMI

Underweight (<18.5) 1 (0.76)

Normal (18.5-24.9) 22 (16.79)

Overweight (25-29.9) 47 (35.88)

59

Obese (≥30) 61 (46.56)

Family history of HS

Yes 34 (25.95)

No 97 (74.05)

Smoking status

Active smokers 57 (43.51)

Ex-smokers 20 (15.27)

Never smoked 54 (41.22)

Hurley stage

I 39 (29.77)

II 47 (35.88)

III 45 (34.45)

HS treatment in last 4 weeks

Topicals alone 24 (18.32)

Topicals plus systemic 107 (81.68)

Currently on biologics for HS

Yes 21 (16.03)

No 110 (83.97)

History of surgical intervention for HS

Yes 47 (35.88)

No 84 (64.12)

60

Table I. Demographics of patients and clinical characteristics

No. (%)

Associated medical diseases, n=49

Asthma 13 (17.81)

COPD 3 (4.11)

Diabetes I 2 (2.74)

Diabetes II 16 (21.92)

Down Syndrome 1 (1.37)

Dyslipidemia 9 (12.33)

Hypertension 12 (16.44)

IBD (Crohn’s) 5 (6.85)

IBD (Ulcerative colitis) 2 (2.74)

PCOS 5 (6.85)

hypothyroidism 5 (6.85)

Anemia, n=131

N 100 (76.34)

Y 31 (23.66)

Associated dermatological diseases n=73

Acne vulgaris 20 (40.82)

Psoriasis vulgaris 9 (18.37)

Anti-TNF induced psoriasis 2 (4.08)

61

Pilonidal cyst/sinus 7 (14.29)

Pyoderma 4 (8.16)

Alopecia 1 (2.04)

Atopic 4 (8.16)

Folliculitis 1 (2.04)

vitiligo 1 (2.04)

Table II. Associated medical diseases in patients with Hidradenitis Suppurativa

Category Total = 131, no. (%)

PGA

Clear (0) 7 (5.34)

Minimal (1) 14 (10.70)

Mild (2) 37 (28.24)

Moderate (3) 34 (25.95)

Severe (4) 17 (12.98)

Very severe (5) 22 (16.79)

IHS4

Mild (≤3) 46 (35.11)

Moderate (4-10) 58 (44.28)

Severe (≥11) 27 (20.61)

Pain score (VAS) category (past 1 week)

None (0) 13 (9.92)

62

Mild (1-3) 32 (24.43)

Moderate (4-6) 52 (39.69)

Severe (7-10) 34 (25.95)

SAHS category

Mild (0-4) 46 (35.11)

Moderate (5-8) 48 (36.64)

Severe (≥9) 37 (28.24)

Table III. HS clinical severity score.

Category No. (%)

BDI Severity Category

Normal (1-10) 68 (51.91)

Mild (11-16) 27 (20.61)

Borderline (17-20) 11 (8.4)

Moderate (21-30) 15 (11.45)

Severe (31-40) 8 (6.11)

Extreme (>40) 2 (1.53)

DLQI category

None (0-1) 13 (9.92)

Small (2-5) 21 (16.03)

Moderate (6-10) 29 (22.14)

Large (11-20) 38 (29.01)

Extreme (21-30) 30 (22.9)

63

Table IV. Beck depression inventory (BDI-22) and dermatology quality of life index (DQLI)

scores

BDI DLQI

Age Number Rho (p-value) Rho (p-value)

Delay in HS diagnosis 131 -0.02 (0.798) -001 (0.912)

BMI 131 -0.01 (0.903) -0.05 (0.557)

Pain score (VAS) 131 0.09 (0.324) -0.02 (0.744)

PGA 131 0.23 (0.009) 0.54 (< 0.001)

IHS4 131 0.20 (0.024) 0.33 (< 0.001)

SAHS 131 0.34 (< 0.001) 0.55 (< 0.001)

Missed work days (past 4 weeks) 131 0.31 (< 0.001) 0.45 (< 0.001)

Bothered work days (past 4 weeks) 131 0.29 (0.009) 0.23 (0.041)

Table V. Spearman’s correlation coefficient for Beck depression inventory (BDI) scores and

dermatology life quality index (DLQI) scores.

BDI severity category DLQI severity category

P-value OR (95% CI) P-value OR (95% CI)

Hurley stage 0.231 < 0.001 2.2 (1.4-3.2)

History of HS surgery 0.857 0.235

HS treatment (past 4 weeks) 0.209 0.123

On biologics for HS 0.011 2.9 (1.3-6.6) 0.065

Surgical intervention for HS (past 4 weeks) 0.887 0.480

DLQI < 0.001 1.1 (1.1-1.2) n/a

BDI N/A

< 0.001 1.1 (1.1-1.2)

64

Pain score (VAS) (past 1 week) 0.017

< 0.001 1.5 (1.3-1.7)

PGA 0.037 1.3 (1-1.6) < 0.001 1.5 (1.2-1.9)

IHS4 < 0.001 1.1 (1-1.1) < 0.001 1.2 (1.1-1.2)

SAHS 0.001 1.2 (1.1-1.3) < 0.001 1.3 (1.2-1.5)

Missed work days (past 4 weeks) 0.003 1.4 (1.1-1.7) 0.012 1.3 (1.1-1.6)

Bothered work days (past 4 weeks) 0.049

< 0.001 1.2 (1.1-1.3)

Table VI. Regression analysis with associated Odds Ratios (OR) and 95% Confidence intervals

(CI) for Beck depression inventory (BDI) scores and dermatology life quality index (DLQI)

scores.

BDI-21 Severity Category Number Median IQR Min Max

Normal

DLQI 68 3.00 7.50 13.00 0.00 30.00

Pain (VAS) score 68 2.00 4.00 6.00 0.00 10.00

IHS4 68 1.00 4.00 6.00 0.00 30.00

SAHS 68 4.00 5.50 7.00 1.00 14.00

Mild

DLQI 27 9.00 15.00 22.00 0.00 28.00

Pain (VAS) score 27 3.00 4.00 7.00 0.00 10.00

IHS4 27 3.00 8.00 12.00 0.00 24.00

SAHS 27 4.00 8.00 10.00 1.00 15.00

Borderline

DLQI 11 8.00 13.00 19.00 1.00 24.00

Pain (VAS) score 11 0.00 3.00 5.00 0.00 7.00

IHS4 11 0.00 7.00 10.00 0.00 16.00

SAHS 11 3.00 7.00 10.00 1.00 12.00

Moderate

DLQI 15 9.00 21.00 25.00 5.00 28.00

Pain (VAS) score 15 4.00 5.00 7.00 3.00 8.00

IHS4 15 3.00 6.00 14.00 1.00 18.00

SAHS 15 6.00 7.00 10.00 4.00 13.00

Severe DLQI 8 16.50 20.00 25.00 1.00 28.00

65

Pain (VAS) score 8 6.50 8.00 9.00 0.00 10.00

IHS4 8 6.50 11.00 21.00 0.00 35.00

SAHS 8 5.50 8.50 14.00 0.00 14.00

Extreme

DLQI 2 23.00 26.50 30.00 23.00 30.00

Pain (VAS) score 2 8.00 9.00 10.00 8.00 10.00

IHS4 2 11.00 16.50 22.00 11.00 22.00

SAHS 2 8.00 8.50 9.00 8.00 9.00 Table VII. Beck depression inventory-21 (BDI-21) (supplementary table)

DLQI category Number Median IQR Min Max

None

BDI-21 13 2.00 4.00 10.00 0.00 34.00

Pain (VAS) score 13 0.00 1.00 5.00 0.00 8.00

PGA 13 2.00 2.00 3.00 0.00 5.00

IHS4 13 0.00 1.00 2.00 0.00 15.00

SAHS 13 2.00 3.00 4.00 0.00 6.00

Small

BDI-21 21 3.00 4.00 8.00 0.00 26.00

Pain (VAS) score 21 1.00 3.00 4.00 0.00 8.00

PGA 21 1.00 2.00 3.00 0.00 5.00

IHS4 21 1.00 2.00 4.00 0.00 11.00

SAHS 21 4.00 4.00 6.00 1.00 12.00

Moderate

BDI-21 29 4.00 8.00 14.00 0.00 27.00

Pain (VAS) score 29 2.00 3.00 5.00 0.00 8.00

PGA 29 2.00 3.00 3.00 0.00 5.00

IHS4 29 2.00 4.00 8.00 0.00 30.00

SAHS 29 4.00 6.00 9.00 3.00 15.00

Large

BDI-21 38 7.00 12.00 17.00 0.00 38.00

Pain (VAS) score 38 4.00 5.50 7.00 0.00 10.00

PGA 38 2.00 3.00 4.00 1.00 5.00

IHS4 38 4.00 7.50 12.00 0.00 24.00

SAHS 38 6.00 7.00 9.00 1.00 11.00

Extreme

BDI-21 30 11.00 18.00 27.00 0.00 55.00

Pain (VAS) score 30 5.00 7.00 8.00 0.00 10.00

PGA 30 2.00 3.00 5.00 0.00 6.00

IHS4 30 4.00 10.00 17.00 0.00 35.00

SAHS 30 6.00 8.50 11.00 1.00 14.00 Table VIII. Dermatology quality life index (DLQI) (supplementary table)

66

HS can impact work absenteeism and presenteeism as reported by many of our HS patients. In

the next chapter, we decided to further investigate the association between the clinical severity

measures and work productivity.

67

V. Impact of Clinical Severity on Work Productivity

in Patients with Hidradenitis Suppurativa

Abdulhadi Jfri1, Elizabeth O’Brien1, Ivan Litvinov1, Elena Netchiporouk1

1Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Rm. L8-

201, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada

Keywords: Hidradenitis, hidradenitis suppurativa, work productivity, absenteeism, presentism

Abstract

Background

Hidradenitis suppurativa (HS) negatively impacts patients’ work attendance and productivity.

Objective

Study aimed to determine and predict absenteeism/presenteeism.

Methods

Single center cross-sectional study conducted from 10/2018-12/2019 assessed

absenteeism/presenteeism in the past 4 weeks, demographics and psychological measures. HS

severity assessed using Hurley stage, Dermatology quality of life index, Beck Depression

Inventory-21, visual analogue scale for pain in the past week, HS Physician Global Assessment,

International HS Severity Scoring System and Severity Assessment of HS.

Results

Among 102/131 employed patients, office jobs 81 (79.4%) vs field 21 (20.59%). Presenteeism in

79 patients (77.45%) with mean (SD) 5.13 ± (5.11) bothered days, absenteeism in 44 patients

68

(43.14%) with mean (SD) 1.76 ± (2.11) missed days. Absenteeism increased 2.5x per Hurley

Staging increase; presenteeism by 8x for work location (office vs. field) (P<0.001).

Limitations

Single center design. Lack of control group.

Conclusion

Hurley staging was the most predictive tool for HS absenteeism/presenteeism. Presenteeism is

more prevalent than absenteeism, and is most impacted by work location.

Introduction

Hidradenitis Suppurativa (HS) is a chronic inflammatory cutaneous disorder that presents with

recurrent episodes of painful inflammatory nodules that form sinuses underneath the skin, and

eventually to scarring in the body folds. (1, 2) HS worldwide prevalence may be up to 4%. (3, 4)

It affects females more than males. (5, 6) Diagnosis of HS can be delayed as much as 7 years.

(7). HS can be classified into inflammatory severe phenotype, mild to moderate follicular, or

mixed phenotypes. (8) The most commonly associated comorbidities are diabetes, hypertension,

hypothyroidism, polycystic ovarian syndrome (PCOS), and inflammatory bowel disease (usually

Crohn’s disease). (9-12)

As a result of its appearance and foul odour, HS lesions have a profound impact on patient

quality of life (QoL), leading to social withdrawal including non-participation in sports and

social activities, isolation, embarrassment, and self-consciousness. (12, 13, 14) The more

advanced the disease and the more it is anogenitally localized, the greater its impact on QoL.

Depression risk ranges from 6-43% (15-18), as are anxiety, pain and high BMI, all of which can

69

impair work productivity. (26) Unemployment among HS patients is roughly 21.3-25.2%, with

disability accounting for 9.4%. (12, 27)

HS pathophysiology remains unclear, although occlusion of the hair follicle resulting from

infundibular keratosis and hyperplasia may be the catalyst. (19-22) A dramatic local immune

response follows follicular rupture, leading to abscesses, painful inflammation, sinus tract

formation and scars. (23) Genetics may play a role, as 30-40% of HS patients report a family

history and several genes that alter hair follicle immune function have been identified in HS

patients. (13-15)

HS treatment includes topical antibiotics, cleansers or intralesional steroid injections for mild

cases; (16, 17) oral antibiotics including tetracyclines with doxycycline, oral clindamycin with

rifampin or Rifampin-Moxifloxacin-Metronidazole, and oral retinoids such as acitretin are

commonly prescribed for moderate HS. (18-22) Local excision of draining sinuses (23) or total

removal of apocrine glands bearing skin can be curative. (24) For severe HS, biologics and anti-

TNF alpha inhibitors such as adalimumab and infliximab are very effective. (13, 14, 25)

Material and methods

Patients

This study was approved by the McGill University Health Center (MUHC) research ethics board

(REB-5282). The ethical principles of the Declaration of Helsinki (1964) and subsequent

amendments and applicable regulatory requirements were followed. The study was conducted at

the dermatology division of the Montreal General Hospital from October 2018 through

December 2019. Adult patients attending the HS specialized clinic were invited to participate if

70

they were aged ≥18 years and literate in English or French. All underwent history and physical

examination, and completed two patient-centric questionnaires on depression and quality of life.

Work productivity was assessed using the modules from iMTA Productivity Cost Questionnaire

(iPCQ).

1. Assessment of clinical severity and psychosocial impact

Patients were examined clinically and assessed for Hurley stage, visual analogue scale (VAS) for

pain in the past week, Hidradenitis Suppurativa Physician Global Assessment (HS-PGA) and

Severity Assessment of Hidradenitis Suppurativa (SAHS).

The VAS for pain grades pain intensity objectively on a unidimensional scale from 0-10. (26)

The Hurley classification categorizes patients’ HS severity into 3 stages: Stage I (mild) when it is

local without scaring or sinuses, stage II differs from stage I by the presence of sinuses and stage

III indicates multiple widespread interconnected abscesses. The classification was originally

designed for selection of the appropriate treatment modality. (27)

The HS-PGA has 6 categories ranging from clear (no lesions) to very severe (over 5 abscesses,

draining fistulas, inflammatory and non-inflammatory nodules). It does not consider the number

of body regions involved but is useful in observing inflammatory progression. (28)

The SAHS score combines three physician-rated items -(the number of involved regions number

of inflammatory and/or painful lesions other than fistula (ILOF); and the number of fistula, with

two patient-reported items: number of new boils or existing boils that flared up during the past 4

weeks; current severity of pain of the most symptomatic lesion in the course of their daily

71

activities using a numerical rating scale (NRS-11) ranging from 0 to 10. Mild disease is defined

as an SAHS score of 4 or less, while an SAHS score of 5 to 8 is moderate and a score of 9

represents severe disease. The SAHS score is not based on identifying different types of lesions

as differentiation is difficult with some patients and its clinical impact is questionable. The

SAHS score simply differentiates between ILOF and fistula. (29)

The Dermatology Quality of Life Index (DLQI) has been used since 1994 to assess the effect of

dermatology disorders on patient quality of life. Its ten questions grade impact from 0 (no effect

on QOL) to 30 (extreme impact on QOL) with 2-5 indicating small impact, 6-10 moderate

impact and 11-20 severe impact. (30)

Beck Depression Inventory-21 (BDI-21) is one of the most commonly used tools for assessing

and grading depression. (31). A score up to 10 is normal; 11-16 indicates mild mood disturbance;

17-20 borderline clinical depression; 21-30 moderate; 31-20 severe; over 40 extremely severe

depression.

2. Assessment of work productivity

HS patient work productivity was assessed by modules of the iMTA iPCQ, which includes two

questions measuring productivity losses due to health-related absence from work and three

questions identifying health-related diminished productivity at work. Absenteeism was assessed

by asking the patient whether they’d missed any work days in the past 4 weeks due to HS and if

so, how many. Presenteeism was assessed by asking patients whether they were bothered

physical or psychologically at work by HS in the past 4 weeks, and if so, on how many days.

They were also asked to grade (on a work productivity scale (WPS) of 0-10) the degree to which

their work productivity was bothered by their HS, with 10 indicating no effect on productivity

and zero indicating no work had been produced. (32)

72

Statistical analyses

Examination of data included distributional assessments and calculation of summary statistics for

all variables (median and IQR for non-normally distributed data, frequencies and percentages for

categorical data). The Wilcoxon Rank Sum and Kruskal-Wallis Tests were used to assess

potential differences in age, delay in HS diagnosis, BMI, VAS for pain in the last week, PGA,

IHS4, SAHS, 4 Week Missed Days, 4 Weeks Bothered Days, and 4 Weeks Bothered Scale by:

Beck Depression Inventory severity categories, DLQI severity categories, Presenteeism Status

and Absenteeism Status. Univariate Logistic Regression analyses were used to evaluate all

variables for potential predictive value on Presenteeism Status and Absenteeism Status. Odds

Ratio’s with corresponding 95% Confidence Intervals are provided for significant results.

Additionally, for dependent variables presenteeism and absenteeism status, the regression

analysis was not repeated controlling for history of surgery related to HS in the previous four

weeks due to lack of significance of the covariate in univariate regression. All analyses were

conducted using STATA® (StataCorp. 2019. Stata Statistical Software: Release 16. College

Station, TX: StataCorp LLC.) and unless otherwise noted were interpreted with a Type I Error

Rate of alpha = 0.05 level of significance

Results

A total of 131 adult HS patients were included, 58% of whom were female and 62.6%

Caucasian. The mean age was 38.11. A first-degree family history of HS was reported in 34

(25.95%). A history of smoking was reported in 77, with 57 active smokers and 20 ex-smokers.

73

Patients were nearly even in their Hurley classification with 39 classified as Hurley I, 47 as

Hurley II and 45 as Hurley III. SAHS score was mild in 46 patients (35.11%), moderate in 48

(36.64%), and severe in 37 (28.24%). Ninety percent of patients reported pain related to HS on

the VAS for pain in the last week, with the majority experiencing moderate pain. The mean (SD)

IHS4 was 7.21 (±7.01). Anemia was prevalent in 31 patients (23.66%). (table. II)

Most patients had been on a combined systemic and topical treatment regimen during the 4

weeks prior to the study. Forty-seven patients had a history of surgical intervention for HS

(incision & drainage, deroofing or complete lesional excision).

Among our 131 patients, 102 were employed, and a total of 44 patients (43.14%) reported

missed days in the previous 4 weeks (absenteeism), with mean (SD) missed workdays of 1.76 ±

(2.11). Presenteeism was more prevalent, with 79 (77.45%) patients reporting either physically

or emotionally bothered workdays of 5.13 ± (5.11). (table. III)

Absenteeism

There were statistically significant differences in the number of days of work missed that were

linked to both DLQI and BDI-21. Overall, patients whose median DLQI and BDI-21 were lower

<11 and <31, retrospectively (i.e. less severe) had less reported absenteeism. The same was true

of the pain VAS in the last week, the HS-PGA, the IHS4 and SAHS. In all cases, the worse the

score, the higher the number of days absent.

Predictions of number of days absent from work relative to changes in the various indexes and

measures: are shown in Table 6. Univariate Logistic Regression Analyses showed evidence of

statistically significant covariates: The odds of absenteeism increased approximately 2.5 times

for each level increase in Hurley Stage (p<0.001); 2 times for PGA (P=0.003); and around 1 time

74

for every unit increase in DLQI score, BDI-21, BMI, pain VAS score in last week, IHS4 and

SAHS.

Presenteeism

As was true in absenteeism, presenteeism also reflected statistically significant differences in the

various scoring indexes and the number of days that HS patients reportedly went to work but

were bothered enough (either physically or psychologically) by their disease for it to affect their

productivity. Those differences correlated positively with to the DLQI and BDI-21. Patients

whose median DLQI and BDI-21 were lower had lower reported presenteeism, while those with

higher statistical measures had higher levels of presenteeism (11.0). The same was true of the

pain VAS score for the previous week, as well as the PGA, the IHS4 and SAHS. In all cases, the

worse the score, the higher the number of days with work product negatively impacted.

Table 7 illustrates predictions of number of days negatively impacted at work relative to

changes in the various indexes and measures: Univariate Logistic Regression analyses showed

the following statistically significant covariates with OR (95% CI): work location (office vs

field) (p<0.001) 7.9 (2.2-28.8), Hurley stage (p=0.004) 2.4 (1.3-4.4), DLQI (p=0.013) 1.1 (1.0-

1.1), pain VAS score in last week (p<0.001) 1.5 (1.2-1.9), PGA (P<0.001) 2.0 (1.3-3.0), IHS4

(p=0.005) 1.1 (1.0-1.3) and SAHS (p=0.005) 1.2 (1.1-1.5).

Discussion

HS can affect work productivity. In a study of 100 HS patients of whom 57 (57.0%) were

employed, 21.2% reported absenteeism from work in the week preceding the study and 60.4%

reported loss of work productivity during the preceding week as a result of HS (presenteeism).

(33) Our study detected a rate of absenteeism for the 4 weeks prior to the study of 43.14%.

75

Another study of newly diagnosed HS patients (n = 1003, mean age 39·5 years, 66·3% female)

and general patients with HS (n = 1204, mean age 39.9 years, 69.1% female) were matched to

5015 and 6020 controls, respectively. Newly diagnosed patients with HS had significantly slower

income growth ($324 per year) and higher risk of leaving the workforce (adjusted hazard ratio

1·65, 95% confidence interval 1·45-1·88) compared with controls (all P < 0·05). General

patients with HS had more total days of work loss (18·4 vs. 7·7), higher annual total indirect

costs ($2925 vs. $1483) and lower annual income ($54 925 vs. $62 357) than controls (all P <

0·001). The study did not examine the impact of the HS clinical severity scores on absenteeism

or presenteeism since the study was done on data extracted from a database. (34)

In a prospective cross-sectional study of 51 HS patients conducted at a community dermatology

clinic in Toronto, Canada, 40 out of 51 were currently employed. Twelve reported HS-related

absenteeism in the past week. Absenteeism was 0 for Hurley stage I and highest for Hurley stage

III 24.6 ± 30, (35)

A study of 54 Polish HS patients (28 women, 26 men) between the age of 16 and 65 years

(mean, 39.94 ± 11.63 years) reported absenteeism due to HS among 30, or 58.1%. Annually, the

absence from work caused by HS occurred from one to 10 times (mean, 2.9 ± 2.4 times).

Furthermore, the mean absence from work during the past year was 33.6 ± 26.1 days (range, 3-

96 days). During 2 years of follow-up, three employees (10%) were dismissed from work

because of their frequent absences and inability to perform their work duties properly. Seven

patients (23.3%) reported being ineligible for promotion or experiencing disease-related

obstacles to promotion or advancement. (36)

76

Comparing work productivity with 98 patients with psoriasis (a similar chronic inflammatory

skin disorder), in the four weeks prior to the study approximately one fifth of employed patients

(19%) had been on sick leave (absenteeism) due to psoriasis and 28% reported having worked

despite being sick with psoriasis (presenteeism). (37) Biologics such as adalimumab have been

shown to improve work productivity in patients with moderate to severe psoriasis. (38)

Conclusion

Presenteeism is more prevalent than absenteeism among HS patients. The clinical severity of HS

(assessed by Hurley staging, pain VAS score in last week, PGA, IHS4 and SAHS) impacts the

quantity and quality of patients’ work. Hurley stage, PGA, IHS4 and SAHS are good clinical

assessment tools for predicting absenteeism and presenteeism among HS patients. Among

severity assessment tools, Hurley stage was the most effective for predicting HS absenteeism and

presenteeism. Presenteeism was greatly impacted by work location (office vs. field).

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76.

Total 131, n. (%)

Sex

Females 76 (58.02)

Males 55 (41.98)

79

Ethnicity

African 17 (12.98)

Caucasian 82 (62.6)

Middle Eastern 10 (7.63)

Native Canadian 8 (6.11)

Asian 7 (5.34)

Latino 7 (5.34)

BMI

Underweight (<18.5) 1 (0.76)

Normal (18.5-24.9) 22 (16.79)

Overweight (25-29.9) 47 (35.88)

Obese (>/=30) 61 (46.56)

Family history of HS

Yes 34 (25.95)

No 97 (74.05)

Smoking status

Active smokers 57 (43.51)

Ex-smokers 20 (15.27)

Never smoked 54 (41.22)

Hurley stage

I 39 (29.77)

80

II 47 (35.88)

III 45 (34.45)

HS treatment in last 4 weeks

Topicals alone 24 (18.32)

Topicals plus systemic 107 (81.68)

Currently on biologics for HS

Yes 21 (16.03)

No 110 (83.97)

History of surgical intervention for HS

Yes 47 (35.88)

No 84 (64.12)

Table I. Demographics of patients and clinical characteristics

Category Total = 131, no. (%)

PGA

Clear (0) 7 (5.34)

Minimal (1) 14 (10.70)

Mild (2) 37 (28.24)

Moderate (3) 34 (25.95)

Severe (4) 17 (12.98)

Very severe (5) 22 (16.79)

IHS4

81

Mild (≤3) 46 (35.11)

Moderate (4-10) 58 (44.28)

Severe (≥11) 27 (20.61)

Pain score (VAS) category (past 1 week)

None (0) 13 (9.92)

Mild (1-3) 32 (24.43)

Moderate (4-6) 52 (39.69)

Severe (7-10) 34 (25.95)

SAHS category

Mild (0-4) 46 (35.11)

Moderate (5-8) 48 (36.64)

Severe (≥9) 37 (28.24)

Table II. HS patient’s clinical severity score.

Working status

Employed 102 (77.86)

Unemployed due to HS 9 (6.87)

Unemployed due to other reason 20 (15.27)

Work location (102 employees)

Office 81 (79.41)

Field 21 (20.59)

Work days missed in the past 4 weeks due to HS (absenteeism)

82

Yes 44 (43.14)

No 58 (56.86)

Mean (SD) missed work days 1.76 ± (2.11)

Work days worked while bothered by HS in the past 4 weeks (presenteeism) (102

employees)

Yes 79 (77.45)

No 23 (22.55)

Mean (SD) bothered work days 5.13 ± (5.11)

Mean (SD) effect on work production during bothered days

(0=no production-10=normal)

7.01 ± (1.51)

Table III. Patient working status, absenteeism and presenteeism

Absenteeism Presenteeism

Age p-value p-value

Delay in HS diagnosis 0.192 0.327

BMI 0.075 0.764

Pain score (VAS) 0.002* <0.001*

PGA 0.001* <0.001*

IHS4 <0.001* 0.006

SAHS <0.001* 0.007

DLQI 0.042* 0.015*

BDI 0.025* 0.074

Table IV. Wilcoxon Rank Sum test for between clinical variables and absenteeism and

presenteeism for 102 employees. * p-value <0.05 statistically significant.

83

Absenteeism Presenteeism

P-value OR (95% CI) P-value OR (95% CI)

Work location (office vs. field) 0.200 <0.001 7.9 (2.2-28.8)

Hurley stage <0.001 2.5 (1.5-4.3) 0.004 2.4 (1.3-4.4)

History of HS surgery 0.335 0.729

HS treatment (past 4 weeks) 0.060 0.358

Surgical intervention for HS (past 4 weeks) 0.912 0.450

BMI 0.027 1.1 (1.0-1.1) 0.438

DLQI 0.025 1.1 (1.0-1.1) 0.013 1.1 (1.0-1.1)

BDI 0.012 1.1 (1.0-1.1) 0.048

Pain score (VAS) (past 1 week) 0.001 1.3 (1.1-1.5) < 0.001 1.5 (1.2-1.9)

PGA 0.003 1.6 (1.2-2.1) < 0.001 2.0 (1.3-3.0)

IHS4 < 0.001 1.1 (1-1.2) 0.005 1.1 (1.0-1.3)

SAHS 0.001 1.3 (1.1-1.4) 0.005 1.2 (1.1-1.5)

Table V. Regression analysis with associated Odds Ratios (OR) and 95% Confidence intervals

(CI) for Beck depression inventory (BDI) scores and dermatology life quality index (DLQI)

scores.

Absenteeism Variables No. Median IQR Min Max

No

DLQI 58 10.00 5.00 17.00 0.00 28.00

BDI-21 58 8.00 4.00 13.00 0.00 38.00

Pain (VAS) score in last week 58 4.00 1.00 6.00 0.00 10.00

PGA 58 2.00 1.00 3.00 0.00 6.00

84

IHS4 58 4.00 1.00 6.00 0.00 22.00

SAHS 58 4.00 3.00 7.00 0.00 15.00

Yes

DLQI 44 16.00 7.00 23.00 0.00 30.00

BDI-21 44 11.00 8.00 21.00 0.00 55.00

Pain (VAS) score in last week 44 6.00 3.00 7.00 0.00 10.00

PGA 44 3.00 2.00 4.00 0.00 5.00

IHS4 44 10.00 4.00 14.00 0.00 35.00

SAHS 44 7.00 6.00 10.00 1.00 14.00

Table VI. (supplementary) Absenteeism

Presenteeism Variables No. Median IQR Min Max

No

DLQI 23 7.00 2.50 13.00 0.00 27.00

Pain (VAS) score in last week 23 1.50 0.00 4.00 0.00 8.00

PGA 23 2.00 1.00 2.00 0.00 5.00

IHS4 23 2.50 1.00 6.00 0.00 16.00

SAHS 23 4.00 3.00 6.00 1.00 13.00

Yes

DLQI 79 13.00 8.00 21.00 0.00 30.00

Pain (VAS) score in last week 79 5.00 3.00 7.00 0.00 10.00

PGA 79 3.00 2.00 4.00 0.00 6.00

IHS4 79 6.00 2.00 12.00 0.00 35.00

SAHS 79 6.00 4.00 9.00 0.00 15.00

Table VII. (supplementary) Presenteeism

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VI. Discussion

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease that is multifactorial. HS

patients mostly report smoking and obesity along with metabolic syndrome. However, some

patients lack these associations. (9-11) Family history is reported in nearly one-third of patients

in the literature as well as in our current cohort which indicate a possible genetic component of

the disease. (68, 69, 96)

Literature review on HS genetics (chapter II) showed that HS can be inherited through affecting

one of the signaling pathways, inflammasome or Notch pathways. The latter usually have severe

phenotype. (96)

The autoinflammatory panel contains the most commonly reported genetic mutations in familial

HS in the literature. Those patients were having follicular-predominant phenotype. After screening

three family members affected by follicular HS (chapter. III), we discovered new variants in MEFV

autosomal recessive (c.2177T>C) and NOD2 autosomal dominant (c.2923C). (96)

Depression ranges between 6 - 43% in patients with HS which is higher than depression

prevalence in general population. (15-17, 75, 97, 98). We investigated the role of depression

screening in HS patients using BDI-21 and we found that depression is underdiagnosed in our

cohort. HS patients with unknown past mental illnesses and screened positive for depression

were 36 patients (27.48%). Furthermore, IHS4 which is used to assess the severity of HS patients

can be used clinically to indicate the need of depression screening in high risk patients.

HS can affect work productivity with literature reported absenteeism of 21.2% and 60.4% of

presenteeism. (99) Some studies reported higher rate of absenteeism in patients with Hurley

86

stage III 24.6 ± 30, (100). In our study of HS and work productivity (chapter 5), we detected a

rate of 43.14% of absenteeism in the past 4 weeks prior to clinical encounter. Presenteeism was

more prevalent than absenteeism among our HS patients. Among various severity assessment

tools, we found that Hurley staging system was the most effective for predicting HS absenteeism

and presenteeism. Furthermore, we found that presenteeism was greatly impacted by the

patient’s work location (office vs. field).

87

VII. Conclusion and summary

HS genetics testing

Literature review on HS genetic supports the genetic role in the pathogenesis of HS. Familial HS

is associated with mutation in autoinflammatory panel. We recommend genetic testing using

autoinflammatory panel in patients with significant family history of HS especially those with

more follicular lesions.

HS impact on psychosocial life

Patients with severe HS clinically measured using IHS4 should be screened for depression using

BDI-21 and offer referral to psychiatry.

HS impact on work productivity

Patients with severe HS measured on Hurley staging system should be screen for absenteeism

and presenteeism. Work location adjustment should be discussed in those with positive

presenteeism.

In summary, HS impact multiple aspects of patients’ lives. More studies are needed to explore

the hidden parts in this debilitating chronic inflammatory disease. In addition, studies

investigating the pheno-genotype classification of HS using complete clinical assessment tools

including ultrasound for staging to better understand the disease more and offer better

therapeutic options to our patients.

88

VIII. LIST OF ABBREVIATIONS

AD: Autosomal Dominant

AID: Autoinflammatory disorders

AMPs: Antimicrobial proteins

APH1: Anterior Pharynx Defective 1

ATP2A2: ATPase type 2 calcium pump

BDI-21: Beck Depression Inventory

BMI: Body mass index

CAPS: Cryopyrin-Associated Periodic fever Syndromes

CCL5: Chemokine (C-C motif) Ligand 5

CerS2: Ceramide synthase 2

DLQI: Dermatology Quality of Life Index

ELOVL7: Elongation of very long chain fatty acids protein 7

FGFR2: Fibroblast Growth Factor-Receptor 2

FMF: Familial Mediterranean Fever

hBD: Human β-defensin 1

HLA: Human leukocyte antigens

HS: Hidradenitis Suppurativa

HSSI: hidradenitis suppurativa clinical severity index

HS-PGA: Hidradenitis suppurativa physician global assessment

IL: Interleukins

IL-12Rβ1: Interleukin 12 receptor β1

IP-10: Interferon gamma-induced protein 10

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iPCQ: Productivity Cost Questionnaire

ILOF: inflammatory and/or painful lesions other than fistula

KID: Keratosis Ichthyosis Deafness

LPIN2: Lipin 2

MDD: major depressive disorder

NCS: Nevus Comedonicus Syndrome

NCSTN: Nicastrin

NLRP3: Nucleotide-binding domain Leucine-rich Repeat containing Protein 3

NRS: numerical rating scale

OCRL1: Inositol polyphosphate 5-phosphatase

PAPASH: Pyogenic Arthritis, Pyoderma Gangrenosum, Acne, and Hidradenitis Suppurativa

PASH: Pyoderma Gangrenosum, Acne, and Hidradenitis Suppurativa

PC: pachyonychia congenita

PCOS polycystic ovarian syndrome

PDE4: Phosphodiesterase 4 inhibitor

POFUT1: Protein O-Fructosyltransferase 1

PSEN: catalytic presenilin

PSENEN: presenilin enhancer 2

PSTPIP1: Proline-Serine-Threonine-Phosphatase-Interactive Protein 1

RNase 7: ribonuclease 7

SAHS: Severity Assessment of Hidradenitis Suppurativa

SERCA: Sarcoendoplasmic Reticulum Calcium Adenosine triphosphatase

SPHK2: Sphingosine kinase 2

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SULT1B1: Sulfotransferase Family 1B Member 1

Th17: T helper 17

TLR2: Toll like receptor 2

TNF-α: Tumor Necrosis Factor-alpha

QoL: quality of life

VAS: visual analogue scale

91

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