Understanding the Relationship Between Smoking and Hidradenitis Suppurativa

Abstract

Hidradenitis suppurativa (HS) is a chronic skin disease affecting hair follicles in intertriginous areas, characterized by deep, recurrent, painful nodules and abscesses, fistulae, sinus tracts, and scarring. With a prevalence of 1-4%, HS is not an uncommon disease. Several risk factors have been linked with the development of HS, such as genetic predisposition, smoking, and obesity, leading to the hypothesis that HS develops as a result of environmental triggers in a genetically susceptible individual. Smoking has been recognized as one of the environmental factors with the most impact on HS. This review aims to provide a comprehensive and holistic view on how smoking habits affect the incidence, severity, treatment, and pathophysiology of HS. A growing body of published literature has reported the association between smoking and HS, despite limitations in proving the causal relationship due to the retrospective design of the available studies. There is a consensus that patients with HS who are active smokers have a higher number of affected body areas than patients with HS who do not smoke or have stopped smoking. Similarly, it is recommended for patients with HS to discontinue tobacco use because of its association with weaker treatment response. Studies on the pathophysiological mechanism of smoking on the skin show that tobacco smoke with many of its chemicals as well as nicotine promote the proinflammatory cytokines found in HS lesions, activate the nicotinic acetylcholine (nAChRs) and aryl hydrocarbon receptors (AHRs), and further suppress Notch signaling pathway.

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ACTA DERMATOVENEROLOGICA CROATICA
Understanding the Relationship Between Smoking
and Hidradenitis Suppurativa
Zrinka Bukvić Mokos, Joško Miše, Anamaria Balić, Branka Marinović
Department of Dermatology and Venereology, University Hospital Centre Zagreb,
School of Medicine University of Zagreb, European Reference Network (ERN) – Skin
Reference Center, Zagreb, Croatia
Corresponding author:
Joško Miše, MD
Department of Dermatology and Venereology
University Hospital Center Zagreb
School of Medicine, University of Zagreb
Šalata 4
10000 Zagreb
Croatia
joskojerolim@gmail.com
Acta Dermatovenerol Croat 2020;28(1):9-13 REVIEW
ABSTRACT Hidradenitis suppurativa (HS) is a chronic skin disease
aecting hair follicles in intertriginous areas, characterized by deep,
recurrent, painful nodules and abscesses, stulae, sinus tracts, and
scarring. With a prevalence of 1-4%, HS is not an uncommon disease.
Several risk factors have been linked with the development of HS,
such as genetic predisposition, smoking, and obesity, leading to the
hypothesis that HS develops as a result of environmental triggers in
a genetically susceptible individual. Smoking has been recognized
as one of the environmental factors with the most impact on HS.
This review aims to provide a comprehensive and holistic view on
how smoking habits aect the incidence, severity, treatment, and
pathophysiology of HS. A growing body of published literature has
reported the association between smoking and HS, despite limita-
tions in proving the causal relationship due to the retrospective de-
sign of the available studies. There is a consensus that patients with
HS who are active smokers have a higher number of aected body
areas than patients with HS who do not smoke or have stopped
smoking. Similarly, it is recommended for patients with HS to discon-
tinue tobacco use because of its association with weaker treatment
response. Studies on the pathophysiological mechanism of smok-
ing on the skin show that tobacco smoke with many of its chemicals
as well as nicotine promote the proinammatory cytokines found
in HS lesions, activate the nicotinic acetylcholine (nAChRs) and aryl
hydrocarbon receptors (AHRs), and further suppress Notch signaling
pathway.
KEY WORDS: hidradenitis suppurativa, acne inversa, smoking, to-
bacco, cigarette
INTRODUCTION
Hidradenitis suppurativa (HS) is a chronic, relaps-
ing, inammatory skin disease that appears as a re-
sult of follicular occlusion and secondary rupture of
the sebofollicular junction of folliculopilosebaceous
units (FPSUs). Consequently, an inammatory cas-
cade occurs, presenting as recurrent, painful, and in-
amed nodules that often rupture and leak purulent
material (1). The chronic timeline of the disease leads

10 ACTA DERMATOVENEROLOGICA CROATICA
to the progression of nodules into abscesses, epithe-
lialized sinuses, stulae, and characteristic “rope-like”
scarring (2).
HS clinically presents at several predilection sites,
rich in apocrine glands, such as the axillae, perianal,
and perineal regions. However, other areas can often
be involved, such as the neck, retroauricular area,
back, inner thighs, scrotum or labia, and the inframa-
mmary and mammary region in women. In women,
inguinal and mammary regions are more commonly
aected, while the anogenital area is more often af-
fected in men (1). The early-stage diagnosis of hidrad-
enitis suppurativa is often missed due to patients rst
presenting to emergency wards or surgical depart-
ments and the general lack of awareness of the sever-
ity of the condition.
The prevalence of hidradenitis suppurativa has
been estimated at 1-4% in the general population (1).
It aects young adults in their early twenties with an
average disease onset at 21.8 years of age. HS is more
frequent among women, except in the age group
above 50 years, because in women the condition
tends to subside after menopause.
Several risk factors have been linked with the
development of HS, such as genetic predisposition,
smoking, and obesity, leading to the hypothesis that
HS develops as a result of environmental triggers in
a genetically susceptible individual. Among the en-
vironmental factors playing a role in HS, smoking
has been extensively researched as dermatologists
and scientists struggle to determine the relationship
between smoking and HS. This review article aims to
summarize the growing body of literature on smok-
ing and HS and to dene the role of smoking in the
development of HS.
METHODOLOGY
An extensive literature review was conducted of
the PubMed and Web of Science databases, as well as
a search on Google Scholar. Using the keywords (hi-
dradenitis suppurativa, acne inversa, smoking, tobac-
co, cigarette), we analysed original scientic articles,
review articles, and letters to the editors.
THE RELATIONSHIP BETWEEN SMOKING
AND HIDRADENITIS SUPPURATIVA: FROM
KARL MARX TO MODERN ERA
Little did Karl Marx know that his smoking habits
and skin condition would be in the center of derma-
tologists’ debate over the relationship between smok-
ing and HS. The debate over the causes of Karl Marx’s
skin condition started in 2007 when Sam Shuster
published that Marx’s incapacitating skin disease was
likely hidradenitis suppurativa (3). Since Marx was a
chronic heavy smoker, dermatologists were quick to
point out that smoking caused one of the most inu-
ential thinkers of the nineteenth century to develop
a debilitating skin disease, which aected his life and
work (4). Others were horried by the idea of using
Karl Marx, one of the symbols of scientic rationalism,
to causally link smoking and HS amidst the lack of
statistical evidence of a causal relationship (5). There
have been several studies assessing the relationship
between smoking and HS even before Sam Shuster’s
essay on Karl Marx. As early as 1997, the rst stud-
ies reported the observation of a high prevalence of
smokers among patients with HS. In 1997, Bassukas
and Hundeiker suggested that toxic tobacco smoke
might contribute to the pathogenesis of HS (6).
Konig et al. assessed the inuence of smoking
habits among 84 patients with HS and found out that
88.9% of their patients with HS were active smokers,
which was a signicantly higher rate than the rate of
active smokers in the matched-pair control group (7).
They further elaborate that it seems to be a rare event
that a never-smoker suers from HS. Happle and Ko-
nig’s later work from 2011 suggests the more specic
term “smoker’s boils” for HS lesions of patients who
are smokers, elaborating that the renaming would al-
low for a correct diagnosis at the initial stage of the
disease. Such a proposal came after several close
statistical relationships between HS and smoking
were reported in several studies (8,9). Newer research
methods, such as radioimmunoassay, have added to
the growing evidence showing that both active and
passive smokers excrete considerable amounts of
nicotine with their sweat (10).
A recent study that investigated HS incidence
among tobacco smokers in a large, diverse cohort of
50 million patients across the U.S. showed that the
odds of a new diagnosis of HS were increased by 90%
among those who smoked tobacco (11).
However, several articles have also been pub-
lished that downplay the importance of smoking as
a risk or triggering factor for HS (12,13). In a French
analysis of 302 medically assessed patients and 67
self-diagnosed patients with HS, current smokers had
12.5- and 4-times higher odds of having HS, respec-
tively (14). However, a history of previous smoking
was not associated with HS, suggesting that smoking
habits may have been a consequence of the disease.
Some authors have even gone further in questioning
the work of Garg et al., implying that their conclusions
about the relationship between smoking and HS go
well beyond what is permissible from the evidence
Bukvić Mokos et al. Acta Dermatovenerol Croat
Hidradenitis suppurativa and smoking 2020;28(1):9-13

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ACTA DERMATOVENEROLOGICA CROATICA
(15). Shuster acknowledges the higher percentage
of active smokers among patients with HS but states
that this fact does not allow the presumption of cau-
sality, accusing some authors of misapplication of as-
sociative epidemiology to etiology (5). Several other
authors also questioned whether smoking increases
the risk of developing HS de novo or is instead a con-
sequence of the disease (high rates of depression and
anxiety among patients with HS; HS inuencing indi-
viduals to smoke tobacco to cope with the psycho-
logical impact of the disease) (16,17).
While there are inherent limitations in retrospec-
tive studies linking smoking and HS, including the
ability to establish a real temporal relationship, there
is a growing body of literature establishing the asso-
ciation between smoking and HS. As clinicians, how-
ever, it is our responsibility to inform every patient
with a dermatological condition about the harmful
eects of smoking on the skin.
TOBACCO SMOKING AND THE SEVERITY
OF HIDRADENITIS SUPPURATIVA
The role of lifestyle factors on HS, such as tobacco
smoking, deserves special consideration as they are
modiable by the patients themselves and could rep-
resent an opportunity for a successful self-mitigating
course for disease remission.
Available studies show conicting results on the
association of smoking with HS severity. Matusiak et
al., in an investigation of 54 Polish patients, found no
signicant correlation between smoking and clinical
severity based on the Hurley scale or with an earlier
onset of the disease. However, there was a signicant
dierence between the group of active smokers and
nonsmokers concerning the number of skin areas af-
fected by HS lesions (18).
Dessinioti et al., in their study of 133 patients, found
that the severity of HS according to Hurley staging
was not associated with current or former smoking
compared with non-smoking. However, similar to the
ndings of Matusiak et al., they reported that current
or former smoking was associated with the number
of aected body areas, i.e. with an increased risk for
active smokers to have more than two body areas af-
fected compared with non-smokers (19).
A study of 115 patients with HS conducted by Sar-
torius et al. reported higher severity HS (according to
the modied Hidradenitis Suppurativa Score (HSS)) in
smokers compared with nonsmokers (20). This nd-
ing might suggest that the recently developed, more
detailed HSS can capture more of the essential clini-
cal information on the patient’s habits than Hurley
staging.
Regarding the cessation of smoking and the re-
mission of HS, Matusiak et al. observed no signicant
alteration in the clinical manifestations of HS in pa-
tients who ceased to smoke (21). However, in study
on 212 patients by Kromann et al., no smoking was
2.8 times more likely to be associated with self-re-
ported remission compared to active smoking (21).
TOBACCO SMOKING AND TREATMENT
RESPONSE
While there are conicting studies on the link
between tobacco smoking and HS, both regarding
occurrence and disease severity, there is a growing
body of evidence suggesting that smoking status in-
uences response to treatment. Kroman et al. showed
that 66% of their patients who reported remission
were nonsmokers and that those who did not smoke
were two times more likely to self-report remission
compared with smokers (21).
A study by Denny et al. found that nonsmokers or
former smokers were almost three times more likely
to have an improvement in their disease compared
with current smokers by being more likely to positive-
ly respond to conventional medical therapies, includ-
ing antibacterial washes/creams/lotions, topical and
oral antibiotics, and intralesional corticosteroids (22).
There is a consensus suggesting physicians
strongly recommend their patients with HS to dis-
continue tobacco use because of its association with
weaker treatment response.
THE PATHOMECHANISM OF SMOKING
EFFECTS ON THE SKIN HELPS US UNDER-
STAND THE INTERESTING CLINICO-EPIDE-
MIOLOGICAL HYPOTHESIS ON THE LINK
BETWEEN SMOKING AND HS
In trying to determine the specic type of relation-
ship between smoking and HS (epidemiological or
causal), we need to delve into the pathomechanisms
of HS and how nicotine and chemicals from tobacco
smoke could induce the formation of HS lesions.
There is a growing body of literature on the patho-
physiology of HS suggesting multifactorial causes to
the emergence of HS phenotype. Cytokines involved
in HS pathogenesis include interleukin (IL)-1β, IL-17,
IL-10, IL-23, and, to a lesser extent TNF-α (23). Their
potent pro-inammatory capacity drives the inux
of immune cells and triggers the inammatory re-
sponse cascade. Studies of the genetic aberrations in
HS found that the loss of function mutations in the
gamma-secretase gene is associated with HS. Since
gamma-secretase cleaves intracellular Notch, the
Bukvić Mokos et al. Acta Dermatovenerol Croat
Hidradenitis suppurativa and smoking 2020;28(1):9-13

defect of the Notch signaling pathway leads to the
formation of follicular keratin-enriched epidermal
cysts and negative regulation of Toll-like receptors,
with a consequent excessive cornication in the pro-
inammatory environment.
Tobacco smoke is composed of many chemicals,
some of which, along with nicotine, propagate the
pathophysiological pathway described in HS. Along
with nicotine, these chemicals activate keratino-
cytes via nicotinic acetylcholine (nAChRs) and aryl
hydrocarbon receptors (AHRs), leading to acantho-
sis, infundibular epithelial hyperplasia, and exces-
sive cornication (24). Nicotine also alters the host’s
defense by inducing the generation of pro-inam-
matory cytokines by keratinocytes, chemotaxis, and
Th17 cell induction (25). Moreover, nicotine elicits
the proliferation of Staphylococcus aureus (26), and
other tobacco smoke components enhance bacterial
virulence by increasing cellular adhesion and induc-
ing biolm production (27,28). A study by Melnik et
al. reported down-regulation of the Notch signaling
pathway in active smokers, suggesting that cigarette
smoke, which is prevalent in HS, may further suppress
already decient Notch signaling in HS (24).
Connecting the damaging eects of tobacco
chemicals and nicotine with the pathomechanism
that causes HS lesions seems to be one of the best
explanations of a causal relationship between smok-
ing and HS.
CONCLUSION
HS is a multifaceted skin disorder with a complex
etiology involving genetic and environmental fac-
tors. An investigation into the etiology and nature of
the disease presents an opportunity to identify and
address modiable risk factors that would potential-
ly alter the incidence and the course of the disease.
Smoking habits have been identied as one of the
risk factors, as it has been observed that many pa-
tients with HS smoke. To scientically prove the exact
causal relationship between smoking and HS, large
multicenter studies are needed instead of retrospec-
tive studies. Even though this relationship is likely to
remain debatable, we strongly encourage patients
with HS to quit smoking as evidence for damaging
pathomechanism eects of nicotine, tobacco smoke,
and its chemicals on skin and HS lesions is convinc-
ing. Thus, this review supports the hypothesis that
environmental triggers, such as cigarette smoking,
may result in the HS phenotype in a genetically sus-
ceptible individual.
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