Department of Medicine, Huddinge Karolinska Institutet, Stockholm, Sweden
CLINICAL ASPECTS OF HIDRADENITIS SUPPURATIVA
Hassan Killasli
Stockholm 2022
All previously published papers were reproduced with permission from the publisher.
Published by Karolinska Institutet.
Printed by Universitetsservice US-AB, 2022
©Hassan Killasli, 2022 ISBN 978-91-8016-710-9
Cover illustration: From an analysis of the original correspondence, it has been possible to establish that Karl Marx's incapacitating skin disease was hidradenitis suppurativa (1) Source of the picture is Wikimedia commons.
Clinical aspects of hidradenitis suppurativa THESIS FOR DOCTORAL DEGREE (Ph.D.)
By
Hassan Killasli
The thesis will be defended in public at Infektiongatan 42, föreläsningssalen, Karolinska Universitetssjukhuset Huddinge, 2022-09-02
Principal Supervisor:
Lennart Emtestam Karolinska Institutet
Co-supervisor(s):
Jan Lapins
Karolinska Institutet
Department of Medicine, Huddinge Karin Sartorius
Karolinska Institutet
Clinical Science and Education, Södersjukhuset
Johan Heilborn Karolinska Institutet
Department of Medicine, Solna Louise Lönndahl
Karolinska Institutet
Department of Medicine, Solna
Opponent:
Lukasz Matusiak
Wroclav Medical University
Department of Dermatology, Venereology and Allergology
Examination Board:
Magnus Lindberg Örebro University
School of Medical Sciences Harry Beitner
Karolinska Institute
Department of Medicine, Solna Desirée Wiegleb Edström Örebro University
School of Medical Sciences
To my family
1
SUMMARY IN SWEDISH
Hidradenitis suppurativa (HS) är en kronisk inflammatorisk hudsjukdom som kännetecknas av återkommande bölder ofta lokaliserade till armhålor och ljumskar. Sjukdomen bildar inflammerade bölder, ärr och fistlar under huden och från dessa områden rinner var.
Sjukdomen är mycket smärtsam och i och med att den drabbar känsliga områden som kring ljumskar och genitalia blir sjukdomen än mer plågsam. Ofta ger varbildningen upphov till dålig lukt vilket ytterligare stigmatiserar sjukdomen och påverkar patienterna negativt ur social synvinkel.
Sjukdomen debuterar vanligtvis i vuxen ålder men den förekommer även hos barn.
Ärftlighet har betydelse för risken att utveckla sjukdomen och man uppskattar att upp till 30% av patienterna med HS har en första- eller andragradssläkting med samma sjukdom.
Andra faktorer som har negativ påverkan på sjukdomen är bland annat rökning, övervikt och friktion.
I delarbete I har vi studerat och validerat ett utvärderingssystem för att kunna bedöma svårighetsgraden av HS, Hidradenitis Suppurativa Score, HSS. En viktig faktor i det kliniska arbetet med HS är att man objektivt kan bedöma svårighetsgraden och därav bestämma vilken behandling som passar bäst, samt följa och utvärdera insatt behandling. Vidare har vi studerat och bekräftat att vissa miljöfaktorer såsom rökning, övervikt försämrar sjukdomen.
I delarbete II har vi studerat vilka typer av bakterier som växer i den akuta fasen av bölderna.
Proverna togs medan vi opererade patienterna med koldioxidlaser för att minska risken för kontaminering. Våra fynd var något överraskande då resultaten inte kunde bekräfta att viss typ av bakterie (S. aureus) växte trots att den vid den här tidpunkten bedömdes som en av de mest sannolikt sjukdomsframkallande. Precis som de flesta studier där man undersöker bakteriefloran vid HS ger olika studier olika resultat, dels beroende på hur man tar proven och dels beroende på vilka analysmetoderna man använder, men också beroende på i vilken fas sjukdomen befinner sig i när provet tas (om det är tidigt eller sent i förloppet). Det är fortfarande oklart hur bakteriefloran påverkar sjukdomsutvecklingen. Vi vet att en infektion som uppstår akut och ger försämring ska behandlas kortvarigt med antibiotika men samtidigt vet vi också att vi inte kan bota HS med antibiotikabehandling.
I delarbetena III-IV undersökte vi, genom Socialstyrelsens databas om olika diagnoser för hela Sveriges befolkning, viktiga aspekter rörande HS. Bland annat kunde vi göra en
uppskattning om hur vanlig sjukdomen är i Sverige idag. Detta är en fråga som vi fortfarande får olika svar på baserat på vilken grupp man undersöker och vilken metod man använder för att studera det. Olika studier ger en uppfattning om att det rör sig om ca 0,1- 4%. I vår studie undersökte vi också samsjuklighet. Vi kom fram till att samsjuklighet är vanligt och det rör sig då främst om andra inflammatoriska sjukdomar som bland annat tarmsjukdomen Morbus Crohn, och psoriasis. Även psykiatrisk samsjuklighet var överrepresenterat i denna grupp.
Vidare analys av vårt material visade att patienter med HS också är en socioekonomiskt
drabbad grupp (lägre utbildning, lägre inkomst, vanligare att leva som singlar, jämfört med resten av befolkningen).
Vi utförde även en analys avseende gravida med HS. Där kunde vi se att kvinnor med HS oftare hade övervikt, fetma och var rökare.
Sammantaget kan man dra slutsatsen att patienter med HS är en drabbad patientgrupp, med ökad risk för bland annat psykiatrisk samsjuklighet och sämre socioekonomisk status. De kan behöva extra stöd och resurser och vi borde vara mer uppmärksamma på psykisk ohälsa. Det kan finnas fördelar med att tillämpa ett multidisciplinärt omhändertagande där man också ser till patienten i sin helhet i det kliniska arbetet.
2 ABSTRACT
Hidradenitis suppurativa (HS) is often a chronic skin disease of unknown etiology characterized by formation of non-infectious inflammatory nodules, abscesses, and suppurating skin tunnels mainly in axillae and groins. The lesions are painful, scarring, malodorous and cause suffering, and social stigmatization.
In this thesis different clinical aspects of HS are studied: continuous development of a clinical scoring system, bacterial colonization, relation to social factors and comorbidities, including mental health.
In study I, the objective is to evaluate the modified Hidradenitis Suppurativa Score (HSS) and to describe the interobserver reliability of the HSS and also to document its correlation with risk factors and disease severity. A total of sixty-one patients were scored in various
combinations according to the HSS protocol: Patients' reports of weight and height, smoking habits etc., were registered, and Dermatology Life Quality Index (DLQI) questionnaires. The results suggest that HSS is simple to use and shows low interobserver variability, and it correlates with selected risk factors, indicating that it reflects a valid estimation of disease severity.
In study II, bacteria isolated from HS lesions during exacerbations of the disease were studied. Patients with HS with acute nodules or abscesses were examined during carbon dioxide laser vaporisation. Bacterial samples were taken from the skin surface (before surgery) and then from the deeper layers (during surgery). Coagulase-negative staphylococci (CNS) were the most common bacteria, but contrary to what we expected, Staphylococcus aureus was not found in any cultures from acute inflammatory lesions of HS exacerbations.
In study III, a registry-based cross-sectional study of social characteristics and comorbidity in all HS patients in Sweden as well as the prevalence of lifestyle factors in Swedish pregnant women with HS was performed. A total of 13,538 HS patients diagnosed with HS in specialized care and a subgroup of 1,368 HS patients who had undergone pregnancy were defined, described, and compared with data from the normal population. The HS patients were more often women, unmarried, and had lower education as well as lower income. The pregnant women with HS showed higher prevalence of overweight, obesity, and smoking.
In study IV, the same population of 13,538 HS patients in Sweden as in study III was used in a registry-based cross-sectional study aiming at investigating the relation between mental health and the disease. The result compared with data from the normal Swedish population,
indicates that HS patients suffer more frequently from psychiatric diseases, including depression, anxiety, mood disorders, autism, and ADHD. The findings are reflected by the fact that psychotropic drugs are more often prescribed to HS patients. Dermatologists should be aware of the important association between HS and psychiatric disorders.
3 LIST OF SCIENTIFIC PAPERS
I. Sartorius K, Killasli H, Heilborn J, Jemec GBE, Lapins J, Emtestam L.
Interobserver variability of clinical scores in hidradenitis suppurativa is low.
Br J Dermatol 2010; 162: 1261-1268.
II. Sartorius K, Killasli H, Oprica C, Sullivan Å, Lapins J. Bacteriology of hidradenitis suppurativa exacerbations and deep tissue cultures obtained during carbon dioxide laser treatment. Br J Dermatol 2012; 166: 879-883.
III. Killasli H, Sartoris K, Emtestam L, Svensson Å. Hidradenitis suppurativa in Sweden: a registry-based cross-sectional study of 13,538 patients.
Dermatology 2020; 236: 281-288.
IV. Killasli H, Lönndahl L, Sartorius K, Lapins J, Sjöstrom K, Svensson Å, Emtestam L. Mental health in Swedish patients with hidradenitis suppurativa.
Manuscript.
Scientific papers not included in the thesis
Ingvarsson G, Dufour DN, Killasli H, Sartorius K, Lapins J, Skau PA, Moseng D, Dinparvar D, Furberg A-S, Jemec GBE, Emtestam L. Development of a clinical Scandinavian registry for hidradenitis suppurativa, HISREG. Acta Derm Venereol 2013; 93: 350-351.
Jahns AC, Killasli H, Nosek D, Lundskog B, Lenngren A, Muratova Z, Emtestam L, Alexeyv OA. Microbiology of hidradenitis suppurativa (acne inversa): a histological study of 27 patients. APMIS 2014; 122: 804-809.
Erlendsson EM, Lönndahl L, Killasli H. Intermittent low-dose corticosteroid therapy for hidradenitis suppurativa: a case series. JAAD Case Rep 2021; 13: 105-108.
V.
VI.
VII.
INNEHÅLL
1 SUMMARY IN SWEDISH ... 1
2 ABSTRACT ... 3
3 LIST OF SCIENTIFIC PAPERS ... 5
4 LIST OF ABBREVIATIONS ... 3
5 INTRODUCTION... 1
6 LITERATURE REVIEW ... 2
6.1 Hidradenitis suppurativa ... 2
6.2 Epidemiology... 2
6.3 Pathogenesis and microbiology of HS ... 3
6.4 Pathogenesis -histological and immunological response in HS... 4
6.4.1 Initial histological changes and pathogenic response ... 4
6.4.2 Progression to and the chronic disease ... 5
6.5 Scoring systems ... 6
6.6 Clinical presentation, diagnosis, screening and prevention ... 7
6.7 Treatment ... 9
6.7.1 Preventive measures ... 9
6.7.2 Topical Agents ... 9
6.7.3 Intralesional Treatment ... 9
6.7.4 Systemic antibiotics ... 9
6.7.5 Topical antibiotics ... 10
6.7.6 Anti-inflammatory Treatment ... 10
6.7.7 Surgery ... 11
7 RESEARCH AIMS ... 13
8 MATERIALS AND METHODS ... 14
8.1 Study I ... 14
8.1.1 Patients... 14
8.1.2 Hidradenitis Suppurativa Score ... 14
8.1.3 Dermatology Life Quality Index ... 15
8.2 Study II ... 15
8.2.1 Patients... 15
8.2.2 Anesthesia and surgical procedure ... 16
8.2.3 Bacteriological sampling ... 16
8.2.4 Microbiological procedures ... 16
8.3 Study III and IV ... 17
8.3.1 Study design and variables ... 17
8.3.2 Patients... 17
8.3.3 Reference populations ... 18
8.3.4 Swedish national registers ... 18
8.3.5 Statistics ... 19
9 RESULTS ... 21
9.1.1 Patients and general results ... 21
9.1.2 DLQI... 21
9.1.3 HSS Scoring ... 22
9.2 Study II ... 26
9.2.1 General results ... 26
9.2.2 Bacterial results ... 27
9.3 Study III ... 31
9.3.1 General results and prevalence ... 31
9.3.2 Socioeconomic status ... 31
9.3.3 Lifestyle Characteristics of HS Patients in the Swedish Pregnancy Register ... 32
9.4 Study IV ... 37
9.4.1 General results ... 37
9.4.2 Mood disorders ... 37
9.4.3 Anxiety diseases ... 38
9.4.4 Personality disorder ... 38
9.4.5 Autism ... 38
9.4.6 ADHD ... 39
9.4.7 Mental and behavioural disorders due to psychoactive substance use ... 39
9.4.8 Antidepressant medication ... 39
9.4.9 Sedatives ... 40
9.4.10 Sleep medication ... 40
10 DISCUSSION ... 43
11 CONCLUSIONS ... 51
12 POINTS OF PERSPECTIVE ... 53
13 ACKNOWLEDGEMENTS ... 57
14 REFERENCES ... 59
4 LIST OF ABBREVIATIONS
BMI Body mass index
CO2 (laser) Carbon dioxide (laser) CNS
CXCL 10 DAMPs
DLQI FD HS
HiSCORE IFN IL n PGA RCT Sp Spp TNF VAS
Coagulase-negative staphylococci C-X-C motif chemokine ligand 10 Damage associated molecular patterns Dermatology life quality index
Folliculitis decalvans Hidradenitis suppurativa
Hidradenitis Suppurativa Clinical Response Interferon
Interleukin Number
Physician global assessment Randomized controlled trial Species (singular)
Species (plural)
Tumor necrosis factor-alpha Visual analogue scale
5 INTRODUCTION
Hidradenitis suppurativa (HS) is still a rather unknown disease. Most physicians are not familiar with it and the diagnostic delay is up till 7 years, and longer in younger and non- smoking patients (2). During the time to diagnosis, HS patients usually meet more than 3 different physicians (most commonly general practitioners, gynecologists, surgeons, and dermatologists) and are misdiagnosed more than 3 times (3).
Increasing disease awareness of HS can facilitate early diagnosis. More defined criteria will facilitate for general practitioners to set the right diagnosis. One simple method is by asking if the patient had an outbreak of boils during the last 6 months with a minimum of two boils in one of the following locations, axilla, groin, genitals, under the breasts or other locations (not specified), e.g. perianal, neck and abdomen. A positive response to the following question has been shown to identify HS patients with a sensitivity of 90% and a specificity of 97% (4).
Much more work needs to be done on different areas to optimize the health care of HS patients. One important aspect of this is developing and optimizing scoring systems to define severity and enable follow up of existing upcoming treatments. Our research group have been working on validation of hidradenitis scoring system (HSS).
An important factor in the pathogenesis of HS is the bacterial infection, and what role bacteria have in the chronic phase versus in the acute phase (exacerbation). This have also been investigated by our research group.
Internationally several studies have been done to describe the epidemiology and comorbidity of HS. One important comorbidity to consider is the patients´ mental health and psychiatric comorbidities that has been shown to be a complicating factor for many patients with HS.
The prevalence of HS in Sweden and the profile of comorbidities have been investigated in the last two register studies presented in this thesis.
6 LITERATURE REVIEW
6.1 HIDRADENITIS SUPPURATIVA
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized abscesses and fistulas developed mainly in skin areas with higher density of apocrine sweat glands.
Smoking, obesity, hormonal factors and genetic predisposition are established etiological factors for HS (5).
In the affected area will develop gradually painful inflamed nodules, abscesses and pus- discharging tunnels known as sinus tracts and fistulas (5).
The disease is known to cause a great impact of general quality of life and has also been associated with socioeconomic factors like lower education, and lower income.
The comorbidities of HS include metabolic and cardiovascular disorders, which contribute to reduced life expectancy.
6.2 EPIDEMIOLOGY
There is a rather wide variation in the reported prevalence of HS in different studies, varying from approximately 0.03-4% (6, 7). Some studies on the American population seem to show lower prevalence. In one large study on 48 million patients a rather low prevalence of 0,1%
(8). In another large database study on approximately 15million people, the authors could report a prevalence of 0.053% (9). Smaller Danish studies have shown a prevalence high as 4,1 and 4,0% (7, 10), and another study, also from Denmark has shown a prevalence 2,1%
(4). A French study could report an estimated prevalence of 1% (11). Our latest study reported of 0.14% in Sweden (12) and this is lower than previously reported in the Nordic countries. The different numbers reported are probably, at least in part, dependant on the method used for collecting data. There seem to be a gap between registry-based studies and self-reported questionnaire-based studies (13). Registry based studies collect data from medical records, and this might exclude patients with milder symptoms that have not yet been diagnosed. This fact, that many patients are underdiagnosed, have earlier been discussed in a
review by Dufour et al. (14). There is also a general delay in diagnosis, estimated in one study by Saunte et al. (2) to 7.2 years that might influence results of registry-based studies.
Difference in prevalence due to ethnicity cannot be completely ruled out. In one study from USA the disease was notable more prevalent in the African American population (30%) than in Caucasians (0.09%) (8). Studies from Japan and Republic of Korea have for example reported low prevalence, 0.03% and 0.06%, respectively (6) (15). However, it has not yet been determined if these differences in populations are due to genetic or environmental factors, or a combination of both.
Several comorbidities have been reported in HS. One of the greatest risks seems to be increased mortality due to cardiovascular events (IR 1.35) (16). Other comorbidities that have been reported are for example gastrointestinal, endocrine, rheumatologic comorbidities. Also, psychiatric conditions like depression have been described in this patient group (17).
6.3 PATHOGENESIS AND MICROBIOLOGY OF HS
The pathogenesis of the disease is not completely understood. It involves, like many other inflammatory skin diseases both genetic susceptibility and environmental factors.
Furthermore, lifestyle factors, hormonal changes and microbiota are important in the disease development and course over time. The factors mentioned lead to an inflammatory process starting around the terminal hair follicles, resulting in hyperkeratosis, a thickening of the horny layer around the infundibulum. These changes occur predominantly in the
intertriginous areas where skin rubs against skin, creating a plugging of the hair follicles and stasis. The disease is not infectious, but skin microbiota is considered to have impact in the worsening of the disease. The bacteria, especially in the capsuled hair follicle, is thought to further influence and activate immunological response. The impact of bacteria on the course of disease has been discussed in many publications. In chronic HS lesions there is an increase in and a colonization with different strains of bacteria, mainly anaerobic. Prevotella and Porphyromonas spp. (18) as well as Streptococcus anginosus, which typically are found in different mucosal sites of the body. Other bacterial strains that have been related is
Staphylococcus (S.) aureus that has been shown to be increased, at least in superficial parts of lesions (19). Also, coagulase negative like S. epidermidis can be found in both superficial and deeper layers of HS lesions (20). However, if these commensal bacteria that is part of the normal skin flora could play a role in the inflammatory process that drives the disease in HS
have been discussed (19). One important factor in this context can be the formation of biofilm increasing the treatment resistance of the bacteria. The property of producing biofilm appears in line with the recurrent nature of HS and this has indeed been described in HS lesions (21, 22). A wide range of bacteria are in fact capable to produce extracellular matrix (biofilm), for example S. epidermidis. The biofilm serve as a protection from external factors, making the bacteria more resistant to antibiotics and immune mediated defence from the host, causing persisting and recurrent infections (23).
6.4 PATHOGENESIS -HISTOLOGICAL AND IMMUNOLOGICAL RESPONSE IN HS
Bacterial infection is, however, not at all sufficient to explain the pathogenesis of the disease.
Bacteria seem to have a role in aggravating the inflammation that drives the disease. The inflammatory process is still not completely understood and based on studies with limited number of patients. In a recent review of Sabat et al. (24) the authors divide the
immunological response into “initial pathogenic response” and “progression to advanced disease”, to simplify explanation.
6.4.1 Initial histological changes and pathogenic response
Local cell damage due to friction in intertriginous areas are thought to be able to take part in the initial development of the inflammatory response in HS. This will be worsened in obese patients and also by a local decrease in sebaceous glands (25) which might further worsen the friction.
The friction will create cell damage and the upregulation of damage associated molecular patterns (DAMPs) and penetration of bacterial components in the skin. These agents will activate resident immunological cells in the skin to produce chemokines and cytokines for exampleTNF-α and IL-1b which will lead to recruitment of immune cells like monocytes and subsets of T-cells. Perifollicular immune cells will release mediators related to
perifollicular hyperkeratosis and infundibular plugging and development of microcomodones.
Nicotine present in the skin, secreted in the sebaceous glands, further increases the
perifollicular hyperkeratosis and follicular plugging. The plugging of the hair follicle leads to bacterial growth and expands the follicle. The content of the plugged follicle may further activate the immune cells leading to more increase in TNF-α and IL-1b.
There are a lot of immune cells present in HS lesions, as nicely summarized in the review of Sabat et al. (24). The immune cells present are mostly dendritic cells and macrophages (26), T cells (27) and neutrophilic granulocytes (28). Moreover, mast cells (29), natural killer (NK) cells, B cells and plasma cells have been described (28).
Another finding is that skin in HS lesions show an increase in IL-10 which is an anti- inflammatory mediator, but in HS it has been postulated to have negative effect by limiting IL-22 production (30), which in turn leads to limited keratinocyte production of IL-20 and together this results in AMP (antimicorbial peptide)deficiency. This might be responsible for bacterial persistence in HS. The authors interestingly state that nicotine also increases IL-10 which may worsen the disease. Furthermore, they argue that sinceTNF-α is another inducer of IL-10, anti-TNF-α treatment might affect the disease partly this way(30).
6.4.2 Progression to and the chronic disease
T cells involved in the pathogenesis are both TH cells and cytotoxic T-cells. Investigation of HS lesions show upregulation of interferon (IFN) y and interleukin (IL) -17, similar to what is found in psoriatic skin (30). Sabat et al. argues in their review that it is likely that T helper (TH) cells (e.g. TH-1 and TH-17) are the source of these mediators (24).
IFNy have several effects. Among others it increases endothelial permeability to immune cells and mediates the production of chemokines for example CXCL10 (C-X-C motif
chemokine ligand 10) that leads to the attraction of more TH1-cells. CXCL10 has been shown to be upregulated in HS lesioned skin (31).
The occluded and dilated hair follicle surrounded by a massive cell infiltrate then ruptures exposing the immune system to bacterial products, keratin filaments and DAMPs which will aggravate the inflammatory process. Levels of TNF α and IL-1b have been analysed in this stage and found to be increased. These substances will mediate the release of
proinflammatory cytokines and chemokines that will attract more inflammatory cells from the blood stream. This will give rise to the formation of subcutaneous nodules and abscesses.
IL-1B also increases production of Matrix degrading proteins like matrix metalloproteinases (MMPs). MMPs can possibly affect and facilitate the rupture of other hair follicles next to the inflammatory process and also to be part of the creation of tunnel formation. Neutrophils are recruited to the area and contribute to the inflammation with cytokine production and pus formation. One such cytokine is lipocalin-2 (32) that in turn mediates the recruitment of more
neutrophils. The accumulation of pus and destruction of extracellular matrix give rise to a progressive pyogenic disease with chronic damage, scarring and fistula formation in the skin.
To summarize, the inflammatory process in HS is complex, showing both features of an neutrophilic dermatosis (inflammasome-driven dominance of IL-1b) with an involvement of TH-1 and TH-17 cells as well as a strong component of anti-inflammatory signalling with IL- 10 (24).
6.5 SCORING SYSTEMS
The disease is unfortunately not easily treated and there is a great need for research in this field. Treatments available and used stretches from topical treatment (azelaic acid and Clindamycin) to biologicals (Adalimumab). There is often a need to combine and
individually customize treatment for the individual patient. To be able to evaluate and find evidence to decide which treatments are effective and meaningful for the patients, we need a good scoring system to measure disease activity and treatment effectiveness. In the recent year there has been several scoring systems established.
The most established clinical scoring system, to measure disease severity, is the Hurley staging system (33). The score measures the number of abscesses, sinuses and scarring in a staging between 1-3 of disease severity. Further development of a more detailed scoring system gave rise to the Hidradenitis Suppurativa Score, HSS, developed in collaboration with Professor Gregor Jemec and our group (34), were the score also took into consideration the involved regions, severity of lesions and distance between lesions. Further attempts to
develop scoring systems more easily used in studies of HS have been made. The Hidradenitis Suppurativa Physician´s Global Assessment scale (HS-PGA) evaluates number of nodules, abscesses and fistulae and divides severity into six levels (clear, minimal, mild, moderate, severe and very severe) (35). To meet the needs of even further being able to measure treatment response in studies another method was developed. The Hidradenitis Suppurativa Clinical Response (HiSCR) (36) measures clinical response and evaluates decrease in inflammatory nodules and abscesses.
However, these scoring systems are good for evaluating the lesions in patients, they are not sufficient for evaluating the total severity of disease or the total disease burden for patients.
One moderately big lesion, giving rather low scoring in any clinical score, can have a big impact on the single patient’s life. Located in the genital/anal area, being severely painful and purulent, can have great impact on the patient’s quality of life, affecting everything from work to exercise, marriage and sexual relations. Some authors have, e.g., Porter and Kimball (R), in order to include these other factors, suggested a combination between clinical scoring systems and Visual Analogue Scale (VAS) for pain. Furthermore, other scoring systems have made attempts to include Dermatology Life Quality Index (DLQI). Such system was
developed to measure disease activity simpler for everyday clinical practice, International HS Severity Score System (IHS4) (37). There was, as mentioned above, an initial thought to include DLQI but this in the end was excluded since it limited the performance of the scoring system. One recently published scoring system where the authors have, in a study founded by Abbvie, successfully included DLQI in addition to clinical evaluation. This scoring system is called HIDRAscore (38).
6.6 CLINICAL PRESENTATION, DIAGNOSIS, SCREENING AND PREVENTION HS even though it is not that uncommon, has not received as much attention in research as one could have wished for. This can be due to different factors; however, one can be the stigma associated to having the disease. Many patients report that they do not want to be open to others about having the disease. This, and the gap in knowledge among colleagues in other specialties, can lead to the reported many years of delay in diagnosis (2) and a great unmet medical need.
HS diagnosis is made depending on morphology (noduli, fistula, scar, sinus tract, abscesses, open or double ended comodones), localization (skin folds), the course of disease, persistent (presence of lesions for at least 6 months) or recurrent and >2 skin lesions occurring or recurring within 6 months) (5, 39).
Furthermore, there are other clinical signs, to support the diagnosis of HS, which can be history or presence of pilonidal sinus, recurrent atypical lesions such as folliculitis in skin fold, and occurrence of typical HS lesions in atypical locations (areas with pressure or mechanical friction such as the inner thighs or the belt region of the abdomen)(40, 41) and a familial history of HS in first and second degree relatives.
Symptoms of typical HS lesions are purulent, malodorous discharge, pain and discomfort during daily life activities (5).
Patients with HS often present with multiple types of lesions simultaneously.
Differential diagnosis for early HS lesions is as a simple as abscess or a furuncle therefore it is common with diagnostic delay up to 7 years (2). For late stage are cutaneous morbus Crohn disease, acne, lymphogranuloma venereum, granuloma inguinale, actinomycoses, steatocystoma multiplex, cutaneous tuberculosis, metastases, cat scratch diseases(5).
Skin biopsy is usually not required for the diagnosis of HS. Because of different morphology (from open comodones to sinus tract) the histopathological characteristics differ accordingly.
In case of uncertainty about the diagnosis, biopsy might be useful to exclude other disorders such as pyoderma gangrenosum, squamous cell carcinoma or lymphomas.
Laboratory blood tests are not used for establishing the diagnosis of HS because there is no HS specific protein.
Routine bacterial cultures are not indicated in HS, but these can be useful in cases infection is suspected more than HS or in cases of secondary infection in HS.
Radiology is also typically not required for the diagnosis of HS, although sometimes MRI might be used in preoperative assessment of fistulation in the anogenital area to exclude the occurrence of fistulas that communicate with the rectum or anal canal (42).
Moreover, in addition to intertriginous areas, HS may develop in other areas (the nape, the trunk, extremities, or the backside of the ears) which also is influenced by sex. For example, the groin, specifically the upper inner thigh, and sub mammary and infra mammary regions are frequently affected in women, whereas armpits, the perineal or perianal regions, and buttocks or gluteal cleft are more affected in men (41, 43, 44).
6.7 TREATMENT
6.7.1 Preventive measures
Like in the other inflammations diseases lifestyle changes is often needed in addition to medical and/or surgical treatment. Weight reduction for improvement of the disease is one example (45) .
Smoking is another example. There is evidence that cessation of smoking might improve the disease course of HS (46).
Further, the design and fabric of undergarments (decrease friction, humidity, heat and skin flora) could play role in the evolution of HS lesions (47).
6.7.2 Topical Agents
Resorcinol (15%), topical disinfectants, such as chlorhexidine, peroxides, and permanganate soaks, are frequently used (5).
6.7.3 Intralesional Treatment
Injection of triamcinolone 10mg/ml into HS lesion in case of flares (48).
6.7.4 Systemic antibiotics
Antibiotic use in HS should be restricted to secondary bacterial infections or in case they have immunomodulatory properties such as tetracycline, ampicillin, ciprofloxacin and rifampicin. Tetracycline is very common to use as maintenance therapy for suppression of neutrophil migration, chemotaxis, and for inhibits matrix metalloproteinase and not for its antibacterial effects (49, 50).
6.7.5 Topical antibiotics
Topical clindamycin twice daily is more effective than placebo (51), and when compared to oral tetracycline 500 mg twice daily found to has equivalent outcomes for Hurley stage I and II (2).
6.7.6 Anti-inflammatory Treatment
Generally, these treatments have higher-quality evidence in contrast to antibiotic in HS (5), 1-Adalimumab
A start dosage of 80 mg of adalimumab at baseline followed by 40 mg weekly
Adalimumab is recombinant human IgG1 anti-TNF monoclonal antibody that binds and blocks the proinflammatory cytokine TNF-α and the first in this class to be approved for treatment of HS (52).
2- Anakinra
100 mg once daily.
Anakinra is a recombinant IL-1 receptor antagonist that inhibits binding of both IL-1α and IL-1β to IL-1 receptors, which are expressed by macrophages and T cells(53). IL-1 levels are elevated in HS lesions and in perilesional skin (2).
3- Ustekinumab
Weight-based dosage (100 kg: 45 mg; >100 kg: 90 mg) at baseline and weeks 4, 16, and every 12 week.
Ustekinumab is a human IgG1κ monoclonal antibody that binds to the p40 subunit of IL-12 and IL-23, blocking the IL-12Rb1 receptor protein of natural killer cells and T cells (54-56).
Specific genetic variations of the gene coding for a subunit of the IL-12 and IL-23 receptor have been shown to be associated with a more severe course of HS (54, 55).
4- Infliximab
Weight-based dosage (5mg/kg) intravenous injections in weeks 0, 2 and 6 then every 8 weeks Infliximab, a chimeric monoclonal antibody, is another anti- TNF antibody recommended for the treatment of HS (57).
There is a large number of on-going clinical trials in HS (studying IL-17 or the p19 subunit of IL-23, PDE4, L-1α, and JAK1(24) ) that hopefully also will uncover some aspects of HS pathogenesis. Furthermore, emerging new therapies will expand treatment options (58).
6.7.7 Surgery
Surgery is required to treat tunnels and scars associated with chronic HS, or in severe chronic lesions that do not respond to medical treatment (24).
A different surgical technique has been used in the management of HS lesions.
1- Localized Excision or Tissue-Saving Methods
Deroofing and skin tissue–saving excision with electrosurgical peeling (STEEP). In deroofing, a probe is used to explore tunnels and only the “roof” is excised. In STEEP, affected tissues are removed by stepwise tangential excisions. The wounds are left open to heal by secondary intention in both methods (59, 60). Recurrence rates are higher than for wide excision procedures.
2- Incision and Drainage
Incision and drainage should be done only in the presence of fluctuant abscesses for pain relief and should keep in mind it will not cure the lesion and has high recurrence rate (61).
This method is only an emergency measure (57).
3- Wide Excision
An excision of a lesion including a margin of disease-free tissue, sometimes include the entire anatomical region (e.g., all axillary skin). In contrary to other methods, it give lower
recurrence rates but greater postoperative morbidity (such as infection, bleeding, and contractures). Large wounds here often left to heal by secondary intention or closed using split-thickness skin grafts or flaps (62-67) resulting in a prolonged recovery and scar
formation. Extensive surgery is mandatory when HS complicate with the presence of cancer
Finally, HS is a multifocal disease often requiring systemic therapy, the choice of therapy is guided by disease severity, based on the available evidence and the clinical response. A standard and clear algorithm for a multidisciplinary treatment of patients with HS is needed, which moreover, considering the therapy of the skin lesions, should include lifestyle- modification measures and the systemic aspects of HS.
7 RESEARCH AIMS
In our projects we had a broad approach focusing of clinically important factors related to the disease. We validated a scoring system and investigated some aspects of the involvement of bacteria. Additionally, we also investigated the epidemiology and comorbidity of HS in Sweden.
The aims of the projects:
Study I
To describe the interobserver reliability of the HSS and further to document its correlation with risk factors and other measures of disease severity.
Study II
The aim of the study was to determine the type of bacteria isolated from deeper portions acute lesions of HS.
Study III
The aims of this study were to investigate and describe social characteristics and comorbidity in all HS patients in Sweden as well as to study the prevalence of lifestyle factors associated with negative impact on health and pregnancy in Swedish pregnant women with HS.
Study IV
The aims of this study were to investigate and describe psychiatric comorbidity, in all HS patients in Sweden.
8 MATERIALS AND METHODS
8.1 STUDY I
8.1.1 Patients
The patients were selected as consecutive clinical cases referred to a center with a special interest in the disease at the Department of Dermatology, Karolinska University Hospital, Solna, Sweden, on 9–11 November 2009. The diagnosis of HS was based on history and clinical presentation at the examination. The studied patients gave informed consent, and the local ethics committee reviewed the protocol. Sixty-five patients were examined, and 63 patients included in the study. One patient did not fulfil the criteria for HS diagnosis, and one had no symptoms of HS during the last 2 years. The patients were asked to complete a standard self-reported questionnaire with background characteristics, e.g., heredity, age at onset of disease, duration, smoking habits, body weight and height, concomitant diseases and medication. Only basic information was recorded, and self-reported height and body weight were accepted as valid in this study. The patients were also asked to complete a Dermatology Life Quality Index (DLQI) questionnaire, described below.
8.1.2 Hidradenitis Suppurativa Score
The previously published proposal (68)for reporting of uniform outcome variables in evaluation of HS has been further developed and shortened for easier use in a clinical setting(34). The following items are assessed by the dermatologist: the anatomical regions involved: axilla, groin, gluteal (left ⁄right) or other region, 3 points per region. The number and scores of lesions (nodule, 1 point; fistula, 6 points) are calculated for each region. The longest distance between two relevant lesions (or size of lesion if single) in each region is recorded as follows: < 5 cm, 1 point, 5–10 cm, 3 points; > 10 cm, 9 points. In each region the answer to the question ‘Are all lesions separated by normal skin?’ is scored as: yes, 0 points;
no (= Hurley III), 9 points. Regional scores are added, resulting in the patient’s total score.
The upper limit of the scale is open(34).
Scoring procedure Sixty-one patients were scored according to the HSS protocol. First, three dermatologists with 16–30 years of clinical experience and special interest in HS (J.L., L.E., J.H.) and one dermatology resident (H.K.) scored eight patients together, where J.L. (one of
the authors of the original description of the score) trained the other three observers to perform HSS correctly. After this training session, another 23 patients were scored
individually and independently by all the four (in four patients only by three) observers to test the scoring concordance. The remaining 30 patients were scored individually by a single observer. Only the results of the patients (n = 23) scored by four observers (in four cases only by three) were included in the interobserver variability analysis, whereas the results of the HSS in all patients (n = 61) were used to investigate the correlation with DLQI, BMI and smoking habits. For this part, in the 23 patients who were assessed by four observers, the score from the dermatologist responsible for the individual patient was used.
8.1.3 Dermatology Life Quality Index
The DLQI20 consists of 10 questions regarding the impact of the skin disease on feelings and different aspects of daily activities during the last week. Each question is scored from 0 (not at all) to 3 (very much). A total of 30 points is the maximum score, where 0–1 is regarded as no effect, 2–5 small, 6–10 moderate, 11–20 very large and 21–30 as extremely large effect on the patient’s life(69). The authorized Swedish translation of DLQI was used in this study.
Statistics Statistical calculations were made in Statistica 9 (StatSoft Inc., Tulsa, OK, U.S.A.).
For the analyses of correlation and comparison of groups, nonparametric methods were chosen: Spearman rank order correlation test, Mann–Whitney test, Kruskal–Wallis ANOVA and median test. For descriptive statistics of the HSS results, median values with interquartile range (IQR) were used. Basic facts about patients as well as DLQI results are described by mean values ± SD. Interobserver concordance was calculated both by the intraclass
correlation coefficient (ICC) and by nonparametric methods: Friedman comparison of
multiple dependent samples, Friedman ANOVA and Kendall coefficient of concordance test.
The range of Kendall concordance is from 0 to +1. Values close to zero represent lack of agreement in the rankings of the variables, while values close to 1 represent perfect agreement in the rankings of the variables among observers
8.2 STUDY II 8.2.1 Patients
The diagnosis of HS was based on the history and clinical presentation on examination. All patients had one or more active inflamed HS nodules in the axillary or inguinal areas, with <
2 weeks since the onset of exacerbation of the particular lesion. The patients were smokers, but otherwise healthy without known comorbidity. The studied patients gave informed consent, and the local ethics committee reviewed the protocol.
8.2.2 Anesthesia and surgical procedure
Following cleansing with 0.05 mg ml chlorhexidine solution, the area was anaesthetized with injections of lidocaine 1 mg ml and adrenaline (Xylocaine with adrenaline; AstraZeneca, Södertalje, Sweden). The solution was injected around and not directly into the affected area to avoid direct contact with infected tissue. A UNILAS 10 600 CO2 laser with SurgiScan scanner (Limmer Laser GmbH, Berlin, Germany) in Powerscan mode, a pseudocontinuous mode with very short (10 ms) pauses, operating at 30–50 W, was used to vaporize the diseased tissue, aiming at complete ablation of diseased tissue and preservation of healthy tissue. The ablation, through vaporization and concomitant heat sterilization of the overlying skin, gave access to material for bacteriological culture from the deeper parts of the HS lesion.
8.2.3 Bacteriological sampling
The bacteriological analysis was performed from samples of HS lesions at two different levels: first at the skin surface and second at a deeper layer of the lesion, approximately 12–
16 mm below the epidermis. The first level is named superficial I and the second deep II. The deeper level was reached by ablation of the overlying diseased tissue (several mm) with CO2- laser vaporization. The two sampling levels could thereby be considered as separate
compartments. At each level, two samples were taken, the first by pressing a soft agar gel with a cross-sectional area of 1 cm2 against the skin for 10 s without rotation; the second was a tissue specimen from a punch biopsy (4 mm). Bacterial sampling was carried out using aseptic technique. The biopsies were put into sterile tubes containing freeze medium and a slice of soft agar with the bacterial bearing surface was cut in a tube containing pre-reduced peptone yeast glucose broth.
8.2.4 Microbiological procedures
The specimens were processed according to standard procedures at the Department of
different colony types were counted and isolated in pure cultures. All isolates were analyzed according to Gram reaction and colony morphology, followed by biochemical tests.
Anaerobic bacteria were identified to genus level by gas–liquid chromatography of metabolites from glucose
8.3 STUDY III AND IV
8.3.1 Study design and variables
In this cross-sectional study national Swedish registers were used to define and study a cohort of patients with the diagnosis HS registered in specialised care. To include a large enough number of patients in the analysis, a period for inclusion of 14 years was used. The specific study variables for the cohort were number of patients and prevalence of HS. Specific study variables for all patients with HS were sex, age, age at diagnosis, marital status, education, occupation (according to The Swedish Standard Classification of Occupations 2012(70), a system for grouping individuals' occupations or duties used in labour market and individual statistics), income and comorbidity in inflammatory bowel disease (Crohn’s disease, ICD-10 K50, and ulcerative colitis, ICD-10 K51) and type 2 diabetes (ICD-10 E11). The entire Swedish population was used as a reference population in presenting of data for study variables. The variables above were analysed for both populations as they were on 31 December 2014.
A subgroup of HS-patients that were registered in the Swedish Pregnancy register during pregnancy was also studied regarding the variables body mass index, self-reported smoking, and self-reported alcohol habits (measured by Alcohol Use Disorders Identification Test(71) score three months prior to pregnancy).The population registered in the Swedish Pregnancy register was used as a reference population for the subgroup. Summary provided in Figure 1.
The study was conducted in accordance with the Declaration of Helsinki and with approval from the regional ethics committee (registration number 2016/742-31/1).
8.3.2 Patients
A study cohort was defined, for which the prespecified variables were studied. All individuals
(excluding primary care) with HS (ICD-10 L73.2) as one of the registered diagnoses in the National Patient Register during the period 2001-2014 were included. The individuals in this group that were still living in Sweden 31 December 2014, verified by registration in the Swedish population registry in the Longitudinal integration database for health insurance and labour market studies (LISA) database, were included in the final study cohort. This cohort is referred to as the HS-population in this article.
A subgroup of the HS-population with at least one registered pregnancy in the Swedish Pregnancy register, during the years 2010-2015 was defined and studied regarding the variables related to lifestyle factors (see above).
8.3.3 Reference populations
The entire Swedish population 31 December 2014, as it is described in the LISA database, was used as a reference cohort for the analyses carried out on the whole HS-population. Data for the reference populations was publicly available aggregated data in public registers and therefore not possible to analyse on an individual level. All individuals with a registered pregnancy during the year of 2014 in The Swedish Pregnancy register were used as a reference population for analyses of the subgroup. The source data on the reference pregnancies was not obtained directly from the registry, but from the registry´s annual report(72).
8.3.4 Swedish national registers
In Sweden, every individual is given a personal registration number at birth. The personal registration numbers are used in virtually all governmental agency and health care
interactions. Governmental agencies, such as The National Board of Health and Welfare and Statistics Sweden have collected information based on these personal registration numbers in registers that now cover all or a very large part of the Swedish population (almost 10 million people). The personal registration numbers enable record linkage between the registers. In this study the analyses of the study cohort were conducted on a dataset created by record linkagebetween the national Swedish registers listed in Table 1. As presented in Table 1, the Swedish Pregnancy registry does not cover the entire period used to define the HS-population (years 2001-2014). Analyses based on this register were therefore conducted to the available data (years 2010-2015).
Anonymised information from the registers was provided by the corresponding responsible governmental agencies. The linkage of data was performed at the individual patient level using a serial number key. The National Board of Health and Welfare was responsible for the linkage of data.
8.3.5 Statistics
Descriptive statistics of the studied variables are presented as percentage of the HS- population in total, in 10-year age-intervals or by sex. Corresponding data on the studied variables for the entire Swedish population is presented for reference, with the purpose of providing a context to the results shown for the HS-population. The data on the Swedish population used in this study was aggregated and statistical tests were therefore not seemed suitable for comparison with the data on the HS-population. In order to make the HS-
population comparable to the reference population, the reference population was age-adjusted in some of the analyses. The age distribution of the HS-population in five-year intervals was used for the age-adjustments of the reference population.
Fig. 1. Flow chart of Materials and Methods. Cross-sectional study of patients with HS in Sweden.
Table 1. National registers used and type of data collected in the study
9 RESULTS
9.1 STUDY I
9.1.1 Patients and general results
Sixty-three patients with HS (46 women and 17 men) with a mean ± SD age of 41.4 ± 14.7 years (range 18–81) were included in the study (Table 1). The reported mean ± SD duration of HS was 13.6±9.3 years (range 1–37). Mean ± SD age at onset was 27.7 ± 14.8 years (range 9–78). Eighteen patients (30%) reported similar symptoms or HS diagnosis in a first-degree relative. Of the 62 patients who answered the question about smoking, 35 (56%) were
smokers, 11 (18%) former smokers and 16 (26%) nonsmokers. On average, the patients were overweight, with a mean ± SD BMI of 29.7±5.9 kg/m² (median 30, range 19–48). The BMI distribution was relatively uneven in the study group, with only 12 (20%) patients reporting normal BMI (between18,5-25 kg/m²). Nineteen (32%) were overweight (BMI 25-30 kg/m²) and 28 (48%) were obese (BMI over 30 kg/m²). Of the 63 included patients, nine (eight women and one man) had Hurley stage I, and seven (five women and two men) had Hurley stage III HS. The majority, 47 patients (75%), had Hurley stage II disease.
Table 1. Characteristics of the patients
9.1.2 DLQI
The mean ± SD DLQI score for the whole group was 11.3±8.6 (median 9, range 0–30). Men scored higher (12.9±9.3, median 12) compared with women (10.8±8.3, median 8). The
highest scores were recorded for question 1 (soreness, pain), 2 (embarrassment, self- consciousness) and 4 (clothing).
9.1.3 HSS Scoring
To test interobserver reliability of the HSS, 23 of the included patients were scored
individually by four (in four cases only three) dermatologists. These 23 patients (15 women and eight men) with a mean ± SD age of 43.1 ± 14.1 years, disease duration of 11.2±5.6 years and BMI 29.3±6.2 kg/m², were considered representative. Two patients had Hurley stage I HS, three Hurley III and 18 patients Hurley II. The results are presented in Table 2 and Figure 1. Statistical analysis showed ICC +95. As HSS is not proven to be linear, a nonparametric analysis was done in addition and showed the same coefficient of agreement, 0.95.
Hidradenitis Suppurativa Score Sixty-one patients were assessed by HSS, as the HSS protocol was not completed in two cases, both with Hurley stage II. The median (IQR) total HSS recorded in the whole group of HS patients was 40 (18–73), range 0–204. There was a statistically nonsignificant difference in median (IQR) HSS between women [39 (16–68)] and men [60.5 (30–95)]. The HSS values differed significantly between Hurley grade I compared with II and III (P < 0.0001; Fig. 2). For Hurley I, the median (IQR) HSS was 8 (6–10), range 0–12, for Hurley II it was 42 (26–72), range 10–183, and for Hurley III it was 119 (73– 147), range 27–204 (Fig. 2). The results showed statistically nonsignificant differences in median (IQR) HSS between the nonsmokers [26 (12–65)], former smokers [30 (10–56)] and smokers [44 (26–108)] (Fig. 3). There was a positive correlation of fair degree (R = 0.40) between BMI and HSS (Fig. 4), but nonsignificant differences in HSS between the BMI groups, with median (IQR) 12 (10–30) for normal weight, 43 (25–58) for overweight and 51 (24–95) for obese patients (Fig. 5). In univariate analysis without Bonferroni correction for multiple comparisons, several of the differences were significant (Figs 2, 3 and 5). The HSS was positively correlated with DLQI to a fair degree (R = 0.48; Fig. 6). Because of the relatively small number of patients studied, the results were not further analysed in subgroups
according to gender.
Table 2.Hidradenitis Suppurativa Score (HSS) values, median and mean ± SD, and Dermatology Life Quality Index (DLQI) for each of the 23 patients with hidradenitis suppurativa scored by the four observers.
Fig 1. Interobserver variation of Hidradenitis Suppurativa Score (HSS) between four observers (n = 23, although in four patients only three observers).
Fig 2. Hidradenitis Suppurativa Score (HSS) vs. Hurley stage for patients with hidradenitis suppurativa (n = 61: nine with stage I, 45 with stage II and seven with stage III disease). The difference between patients with stage I compared with stage II and stage III was significant (P <
0.0001, Kruskal–Wallis test). If analyzed without Bonferroni correction for multiple comparisons, the difference between Hurley II and III was also significant (P = 0.02).
Fig 3. Hidradenitis Suppurativa Score (HSS) vs. smoking category for patients with hidradenitis suppurativa (n = 60: 15 nonsmokers, 11 former smokers and 34 smokers). There were nonsignificant differences in HSS between the groups (Kruskal–Wallis test). If analyzed without Bonferroni
correction for multiple comparisons, the difference in HSS between former smokers and smokers was significant (P = 0.03).
Fig 4. Scatter plot of Hidradenitis Suppurativa Score (HSS) vs. body mass index (BMI), n = 57. This showed a fair degree of correlation according to Spearman (R = 0.40; P = 0.002).
Fig 5. Hidradenitis Suppurativa Score (HSS) vs. body mass index (BMI) category for patients with hidradenitis suppurativa (n = 57: 10 with normal BMI, 19 overweight and 28 obese). The difference between the groups was not statistically significant (Kruskal–Wallis test). If analyzed without Bonferroni correction for multiple comparisons, the difference in HSS between normal weight and obese patients was significant (P = 0.02).
Fig 6. Scatter plot of Hidradenitis Suppurativa Score (HSS) vs. Dermatology Life Quality Index (DLQI) (n = 56). This showed a fair degree of correlation according to Spearman (R = 0.48; P <
0.001).
9.2 STUDY II
9.2.1 General results
Basic characteristics and stage according to Hurley of the patients are shown in Table 1. Nine patients had not received systemic or local antibiotic for at least 6 months, and one of the 10 patients had stopped using topical clindamycin the last 2 months before the procedure.
Table 1. Basic characteristics of the 10 study patients with exacerbation of hidradenitis suppurativa.
9.2.2 Bacterial results
All patients were culture positive for aerobic bacteria (Tables 2 and 4) from at least one level and one method used to identify the bacteria. Seventy per cent of the tested patients had anaerobic bacteria (Tables 3 and 5). Polymicrobial growth was found in all the patients. No patient was found to have negative cultures with either of the sampling methods. After
coagulase-negative staphylococci (CNS) and Corynebacterium spp., anaerobic Gram-positive cocci were the most common bacteria. The quantitative results of the cultures for each patient are presented in Tables 4 and 5.
Aerobic bacteria CNS were found in superficial agar gel sampling in all but one of the 10 studied cases, and in all deep agar gel samplings (Tables 2 and 4). Tissue cultures from both levels were positive for these species in eight cases. Alpha-haemolytic streptococci were detected in two cases from superficial agar sampling and in one of the deep biopsies.
Micrococci were found in both superficial and deep sampling; in total, six of the patients were colonized with these bacteria. Streptococcus anginosus was found in one (superficial) biopsy. The patient had a polymicrobial flora with a large variety of other aerobic and anaerobic bacteria (Tables 4 and 5). Ninety per cent of the patients carried the facultative anaerobic Corynebacterium spp. either at superficial or deep level. Overall, a predominance of aerobic bacteria was identified in superficial levels. The aerobic bacteria were found in deep levels in 17 of 29 (59%) positive cultures (Tables 2 and 4). Quantification of aerobic bacteria showed a variation between 2-3 and 4.1 colony forming units (CFU) cm)2 in agar,
were the most common anaerobes identified in this study (Tables 3 and 5). They were found in seven patients (seven samples at superficial levels and five samples at deep levels).
Anaerobic Gram-positive rods were identified in superficial samples in three patients, and in deep samples in two patients. Clostridium spp., Prevotella spp. and Propionibacterium spp.
were all found in three patients. One patient had a positive culture for Propionibacterium acnes and one patient Veillonella spp. Quantification of anaerobic bacteria showed a variation between 2.3 and 5.6 CFU cm)2 in agar, and 2.0 and 7.2 CFU g)1 in tissue cultures (Table 5).
Table 2. Results from aerobic bacteriological cultures performed at two levels and by two sampling methods (agar gel and biopsy), of acute hidradenitis suppurativa nodules in 10 patients
Table 3. Results from anaerobic bacteriological cultures performed at two levels and by two sampling methods (agar gel and biopsy), of acute hidradenitis suppurativa nodules in 10 patients
Table 4. Quantitative results [colony forming units (CFU) cm)2 for agar gel, CFU g)1 for biopsies]
from aerobic bacteriological cultures performed at two levels and by two sampling methods (agar gel and biopsy), of acute hidradenitis suppurativa nodules in 10 patients.
Table 5. Quantitative results [colony forming units (CFU) cm)2 for agar gel, CFU g)1 for biopsies]
from anaerobic bacteriological cultures performed at two levels and by two sampling methods (agar gel and biopsy), of acute hidradenitis suppurativa nodules in 10 patients
9.3 STUDY III
9.3.1 General results and prevalence
Characteristics of the HS Population In total, 14,361 individuals were diagnosed with HS in specialized care during the years 2001–2014. Of these, 823 were not living in Sweden on December 31, 2014, and were excluded from further analysis. The remaining cohort of 13,538 patients (referred to as the HS population) were included in the study. This equals a prevalence of HS of 0.14% (based on a Swedish population of 9,747,355 individuals in December 2014). The cohort of 13,538 patients consisted of 10,197 (75%) women and 3,341 (25%) men. The sex distribution in the reference population was 4,875,115 (50%) women and 4,872,240 (50%) men. Based on this, the prevalence in Sweden of HS was 0.21% for women and 0.07% for men. The mean ± SD age of the HS population was 44.2 ± 14.7 years (range 15–100 years). Approximately two thirds of the HS population were between 25 and 54 years of age (Fig. 2). For comparison, in the reference population, one-third of the population was within this age interval. The mean age at which each patient in the HS
population first received the diagnosis of HS in specialized care was 37.2 ± 14.2 years (range 1–91 years; age distribution is shown in Fig. 3).
9.3.2 Socioeconomic status
The HS population was further characterized with regards to marital status, highest completed education, occupation, and income. Compared to the age-adjusted reference population, it was less common for the HS population to be married and more common to be divorced (Table 2). Thirty-six percent of the HS population were married compared to 44% in the Swedish reference population. Regarding education, the highest completed education for each individual is shown in Figure 4. Sixty-eight percent of the HS population had an upper- secondary school degree or higher. This is lower than in the age-adjusted Swedish reference population, where the corresponding result was 82%. Also, it was less common in the HS population to have completed a post-secondary education compared to the Swedish reference population (22 and 38%, respectively). The analysis of individuals with a registered
occupation (Table 3) does not indicate any apparent difference in the distribution of
occupations between the HS population and the Swedish reference population. The results of the analysis of taxable income (Fig. 5) are presented in the currency Swedish kronor (SEK).
At the time of writing this article the value of SEK 100 was GBP 8.55 or USD 11.41. A substantial percentage of individuals (39%) in the HS population had an income of SEK <
100,000 a year. In the age-adjusted reference population the corresponding result was 16%.
The indicated difference in income levels between the HS population and the reference population applies for both women and men. Registered comorbidity in the studied HS- associated diseases was 8% (1,040/13,548) for type 2 diabetes and 3% (441/13,548) for inflammatory bowel disease. These results are not suitable for comparison with prevalence data for the entire Swedish population as the groups differ substantially in composition, for example, regarding age and sex. Adjustments for age and sex was not possible in this
analysis, due to the fact that only aggregated data for the reference population were available.
9.3.3 Lifestyle Characteristics of HS Patients in the Swedish Pregnancy Register
The subgroup of women in the HS population that had one or more pregnancies registered in the Swedish pregnancy register during 2010–2015 consisted of 1,368 individuals. For these, a total of 1,724 pregnancies were registered. Not all studied variables were reported for all pregnancies in the register. See Table 4 for the total number of analyzed pregnancies per variable. A total of 97,328 pregnancies were registered for the reference group of women in the Swedish pregnancy register during 2014. The mean age of the pregnant women in the HS population was 30.2 ± 5.1 years (range 18–45 years) and the mean age was 30.7 years in the reference group. Results of the lifestyle factor characterization is presented in Table 4. Of the pregnancies in the HS population 31% of the women were overweight (BMI 25–29.9) and 27% obese (BMI 30≥) when measured at pregnancy week 12. Further, in 41% of the pregnancies smoking was reported (3 months prior to the pregnancy), and in 9% of the pregnancies hazardous or harmful drinking habits was reported (3 months prior to pregnancy). The corresponding results for the women in the reference group was 26%
overweight and 13% obese, 13% reported smoking, and 5% reported hazardous or harmful drinking habits.
Fig. 2. Age distribution on December 31, 2014, in 10-year intervals. a The HS population (n = 13,538). b The Swedish reference population (n = 9,747,355).
Fig. 3. The age at which each patient in the HS population first received the diagnosis HS in specialized care (n = 13,538). The average age was 37.7 years. Almost half the patients (48%) were aged between 25 and 54 years at the time of the first registered HS diagnosis.
Fig. 4. The highest completed education for each individual in the population on December 31, 2014 (primary school corresponds to 6 years of school, secondary school to 9 years, and upper-secondary degree to 12 years of education). a The HS population (n = 13,538). Sixty-eight percent had an upper- secondary degree or higher. b The Swedish reference population (n = 7,131,607), aged 16–74 years.
Eighty-two percent had an upper-secondary degree or higher.
Fig. 5. Annual taxable income of the individuals (aged 16 years or older) in the populations, expressed in thousands of Swedish kronor (SEK), 2014. Results are displayed for the entire groups and for men and women separately. Taxable income includes all income (except capital gain) from employment and pension, social, unemployment, and welfare benefits. a The HS population (n = 13,507). Thirty- nine percent had a taxable income lower than SEK 100,000. b The age-adjusted Swedish reference population (n = 7,801,143). Sixteen percent had a taxable income lower than SEK 100,000.
Table 2. Marital status in the HS population and the Swedish population, December 31, 2014.
Table 3. Registered occupations in the HS population and the Swedish population, December 31, 2014.
Table 4. Lifestyle factor characteristics of pregnant women in the HS population and the Swedish population.
9.4 STUDY IV
For studying mental health status in HS patients in Sweden we considered several diseases related to mental health diagnosis like mood disorder, anxiety disorder, personality
disorder, autism, ADHD, using of medication as antidepressant, tranquilizer, and sleep pills, and lastly mental and behavioural disorder due to the use of psychoactive substance.
Based on their age we divided studied populations into three different age groups (15–29, 30–59, 60+), and each age category was further divided to men and women and then we compared them with respective strata in the normal Swedish population.
9.4.1 General results
In the general population the prevalence of psychiatric diagnosis is 5.7% compared to 12,2% in HS population. Furthermore, in the general population, a higher percentage of women have a psychiatric diagnosis compared to men in the same age categories, while in HS population, a difference is seen in each age category. The prevalence in the age group 15–29, was 11.3% of men and 12.5% of women, this increases for men in the age group 30–59 to 13.2% but decreases for women to 11.9% in the same age group. To end up at 60+
approximately the same outcome with 6,5% for men and 6.6% for women.
In the age group 15–29, women have a higher percentage of mental illness compared to men, but in the age category 30–59, the proportion of men with mental illness is higher compared to women. Middle-aged men were 1.9% more affected compared to those aged 15–29, and at age 60 the proportion of affected sees a steep decline to 6.5% compared with 13.2% when they were between 30–59 years of age. In women, a minimal reduction of 0.6% is seen between age groups 15–29 and 30–59, and at 60+ it decreases to 6.6%.
9.4.2 Mood disorders
In category 15–29yr, 4.3% (2.9% men and 4.8% women) of HS patients are diagnosed with mood disorders, compared with 1.4% (1.0% men and 1.8%women) in the general
population.