Review

Smoking and the skin

Arisa Ortiz, MD and Sergei A. Grando, MD, PhD, DSc

Department of Dermatology, University of California-Irvine, Irvine, CA 92697, USA Correspondence Dr. Sergei A. Grando, MD, PhD, University of California Irvine 134 Sprague Hall Irvine CA 92697 USA E-mail: sgrando@uci.edu Conicts of interest: None.

Abstract
Cigarette smoking has been associated with signicant morbidity affecting all systems of the body, including the integumentary system. We review the many dermatologic hazards of tobacco use. It is important to distinguish between the effects of tobacco smoke from effects of pure nicotine on the skin. All skin cells express several subtypes of the nicotinic class of acetylcholine receptors, including the a7 receptor. Many chronic dermatoses are affected by smoking either negatively or positively. Elucidation of positive associations with a particular disease can lead to improvement from smoking cessation, whereas inverse correlation may lead to development of a disease-specic treatment with nicotinergic agonists.

DSc

Toxic constituents of tobacco products Cigarette smoking has been associated with signicant morbidity affecting all systems of the body, including the integumentary system. Regardless of efforts made to warn the public regarding the dangers of smoking, smoking remains the leading cause of preventable death. Tobacco smoking has been around since Christopher Columbus observed the American Arawak Indians smoking tobacco leafs in 1492. The tobacco plant was named Nicotiana tabacum after the French ambassador to Portugal, Jean Nicot, who introduced the plant to France. Nicotine, the primary alkaloid found in tobacco, was isolated in 1828. Nicotine can enter the human body by smoke inhalation, ingestion, intranasal spray, transdermal patch, topical cream, or enema. Nicotine occurs naturally in small quantities in certain foods such as tomato, potato, and eggplant. Nicotine can be absorbed through the oral cavity, lung, bladder, gastrointestinal tract, and skin. Seventy to 80% of nicotine absorbed from the gastrointestinal tract is converted to its principal metabolite, cotinine, via rst-pass hepatic metabolism.1 Nicotine is absorbed through skin and mucous membranes in a dose-dependent manner. The half-life of nicotine is approximately two hours.2 There are many dermatological hazards of tobacco use that can affect the skin both directly on the epidermis and indirectly via the bloodstream. Tobacco smoke is comprised of a solid particulate phase, including the alkaloid, nicotine, and a volatile gas phase. There are
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many mutagens and carcinogens in tobacco smoke, notably polycyclic aromatic hydrocarbons, nitrosamines, and heterocyclic amines. The main toxic constituents of the solid phase include nicotine, phenol, catechol, quinoline, aniline, toluidine, nickel, N-nitrosodimethylamine, benzopyrenes, benzanthracene and 2-naphthylamine. The main toxic constituents of the gas phase include carbon dioxide, carbon monoxide, hydrogen cyanide, nitrogen oxides, acetone, formaldehyde, acrolein, ammonium, pyridine, 3-vinylpyridine, N-nitrosodimethylamine, and N-nitrosopyrrolidine. Studies of gene expression in the skin revealed that tobacco constituents upregulate 14 different genes involved in xenobiotic metabolism, oxidative stress, and stress response.3 Tobacco also has non-genomic effects resulting, in part, from activation of reactive oxygen species. Nicotine and other pharmacologically related compounds exert their effects on the skin by activating nicotinic acetylcholine receptors (nAChRs) expressed by skin cells.4 Mucocutaneous signs of smoking Heavy smokers can typically be identied by characteristic cutaneous and mucosal manifestations. Classic ndings include a yellow discoloration of light-colored mustaches and ngernails that are stained by tobacco byproducts. With smoking cessation, a demarcation appears between the distal pigmented nail and growth of the normal nail. This is termed a Harlequin nail, or quitters nail (Fig. 1). The duration of smoking cessation may be deduced by
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(a)

(b)

Figure 1 Harlequin or quitters nail. (a) Nicotine staining and line of demarcation involving several ngers. (b) The demarcation line between the distal pigmented yellow nail and a newlydeveloped proximal pink nail appeared after sudden cessation of smoking (with permission from Ref. 126)

the length of normal nail growth. Chronic heating from holding lit cigarettes may also discolor the ngertips due to post-inammatory hyperpigmentation. One-third of smokers have visible oral pigmentation.5 Gingival pigmentation can also be observed in children exposed to secondhand smoke6 and with sublingual nicotine use.7 Gingival pigmentation is derived from melanin granules that are synthesized in melanosomes. Nicotine, which can act as a precursor in melanin synthesis, is capable of irreversibly binding melanin and accumulating in melanin-containing tissues.8 Other tobacco constituents, specically the carcinogens N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo(a)pyrene, also have been shown to accumulate in tissues containing melanin.9 Smoking may exert effects on the tongue, palate, and other anatomical structures of the oral cavity. Black hairy tongue, characterized by hyperplasia of the papillae with black pigmentation on the dorsal surface of the tongue, may be seen in smokers. Smokers tongue (a.k.a. leukokeratosis nicotina glossi) is a uniform keratosis with inamed salivary glands that appear as umbilicated pap-

ules. Central papillary tongue atrophy may occur in smokers of bidi (tobacco wrapped in a tendu leaf), which is reversible with smoking cessation. Smokers palate (a.k.a. leukokeratosis nicotina palati) is an asymptomatic, uniform keratosis of the posterior two-thirds of the hard palate with multiple red umbilicated papules that represent inamed salivary glands. This is seen exclusively in smokers, especially in heavy pipe smokers. On the other hand, snuff dippers develop a white discoloration at the site where the tobacco is held, which may ulcerate (Fig. 2). Precocious skin aging The most common manifestation of smoking, and perhaps the most socially distressing, is precocious aging. A smokers face characteristically has prominent wrinkles, a gauntness of facial features with prominence of the underlying bony contours, an atrophic, gray appearance of the skin, and a plethoric complexion.10 The degree of aging correlates with the number of packs smoked per day and pack-years of smoking (Fig. 3).11

(a)

(b)

(c)

(d)

Figure 2 Tobacco pouch keratosis (a.k.a. Snuff dippers lesion or smokeless tobacco keratosis). Hyperkeratosis with various degrees of clinical manifestation has developed on those mucosal sites where the tobacco was held. Degree 1 (a) has the color of normal mucosa with a minor degree of supercial early wrinkling. The wrinkles disappear when the lesion is stretched. Degree 2 (b) is a combination of white-gray and reddish areas with moderate wrinkles. Neither wrinkles nor colors disappear when the lesion is stretched. Note the difference in wrinkle thickness in advanced degree 2 (c). Degree 3 (d) has a color similar to that seen in advanced degree 2 (white-gray and reddish), but the mucosa has pronounced thick wrinkles that do not disappear when stretched. The longer the habit the higher the degree. The patient in (d) has an area of early ulceration on the upper portion of the snuff pouch. Cessation of the habit, especially if it is not of long duration, eventuates in disappearance of the lesion (with permission from Ref. 127)
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Twin 1

Twin 2

Figure 3 Smokers face in a smoker twin. Note signicant differences of appearances of the smoking twin 1 and non-smoking twin 2. Twin 1 has a smoking history of approximately 52.5 pack-years, i.e. number of packs of cigarettes smoked per day multiplied by the total number of years smoked. Both twins have similar cumulative lifetime history of sun exposure (with permission from Ref. 11)

This risk is higher in women compared with men. The appearance of wrinkles is exaggerated by direct contact of cigarette smoke, which reduces moisture levels in the stratum corneum and induces a mild inammatory reaction.12 In vivo experiments in mice also show that passive tobacco smoke exposure induces premature skin aging.13 Skin exposed to cigarette smoke is thin and fragile, tending to sag. While cigarette smoking is an independent risk factor for skin wrinkling, there is a synergistic effect with sun exposure on skin aging.14 Smoking also affects sun-protected skin. The number of cigarettes smoked per day and age are the two best predictors of the degree of aging in these sites.15 Cigarette smoke is an important accelerator of the aging process through the formation of free radicals and induction of related pathologies (Fig. 4).16 Smoking may exhaust cellular defense and repair functions, resulting in an accumulation of damage due to mutations and malfunctioning proteins. Smoking also alters extracellular matrix turnover in the skin,17 leading to an imbalance between biosynthesis and degradation of dermal connective tissue proteins. While smoking downregulates synthesis of type I and type III collagens, a major factor for accelerated skin aging,18 it also elevates tropoelastin and increases collagen degradation.19 Smoking is an independent risk factor for the increase of elastic bers in the
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reticular dermis of non-exposed skin. This increase results from degradation of elastic material in an additive manner, as in solar elastosis.20 The disruption of the connective tissue matrix might contribute to the molecular basis for premature skin aging in smokers. In vitro experiments demonstrate that colla-

Figure 4 Mechanism of smoking-induced precocious aging. Smoking increases reactive oxygen species (ROS) and MMP, which leads to collagen degradation and weakening of the structural integrity of the extracellular matrix. This reduced mechanical tension in broblasts results in increased intracellular levels of oxidants, which in turn, stimulate further expression of MMP-1 (with permission from Ref. 128)
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gen biosynthesis by cultured broblasts is signicantly reduced following treatment with tobacco smoke extract.18 Smoking upregulates expression of matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, and MMP-8.17,19 Compared with nonsmokers, the level of MMP-8 is elevated, and TIMP-1, the MMP inhibitor, is decreased in the skin of smokers. Elevated MMP-1 gene expression is also observed in sun-protected skin of active smokers.21 In vitro experiments reveal that tobacco smoke extract can raise the expression of MMP-1 and MMP-3 in dermal broblasts. Moreover, MMP-1 expression is signicantly increased in broblasts after stimulation with both tobacco smoke extract or UVA1 irradiation independent of each other.18 Transforming growth factor (TGF)-b1 may play a role in the age-related cutaneous alterations induced by tobacco smoke. Tobacco blocks cellular responsiveness to TGF-b through the induction of a non-functional form, and downregulation of the TGF-b1 receptor, suggesting a role for modulation of TGF-b1 as a way to delay premature skin aging.22 The tobacco constituent, nicotine, can alter dermal remodeling through an increase in cell cycle regulators, apoptosis regulators, collagen Ia1, elastin and MMP-1.23 Nicotine can exert its effect on cell senescence by altering extracellular matrix metabolism and expression of nAChRs. It favors overproduction of elastin and overexpression of keratinocyte a7 nAChR. The nicotinergic effects on human dermal broblasts, however, are predominantly mediated by the a3 nAChR subtype.24 Skin cancer Epidemiological studies demonstrate both positive and negative correlations between smoking, incidence, and aggressiveness of certain types of skin cancer. The mechanisms of smoking-induced skin cancer include accelerated senescence, mutagenesis, stimulation of tumor cell growth and invasion, neovascularization, and stromal remodeling. While few studies showed no association with smoking,25 the majority of studies have established smoking as an independent risk factor for developing cutaneous squamous cell carcinoma (SCC).26 In particular, smoking is associated with an increased risk of SCC of the penis, vulva, cervix, and anus. Cessation results in a reduction of this risk.27 Smoking increases the frequency of highgrade SCC of the vulva and reduces survival. Female smokers with genital warts are 35 times more likely to develop vulvar cancer, which suggests a synergistic effect between smoking and genital warts.27 An association between oral cancers and smoking also has been well documented.28 Smoking without a lter increases this risk.29 Female smokers are especially susceptible to the risk of developing oral SCC.30
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Most studies have not found a clear relationship between smoking and the risk of basal cell carcinoma (BCC),26 but the evidence is conicting. Cigarette smoking may be associated with an increased prevalence of larger BCCs (>1.0 cm in diameter)31 and more aggressive forms.32 Earlier studies investigating the associations of smoking and melanoma indicated that the proportion of male smokers free of disease ve years after diagnosis was signicantly lower than that of male nonsmokers.33 Smokers were more likely to have metastases on initial presentation, visceral metastases, and metastases within the rst two years after diagnosis.34 More recent studies, however, suggest that the risk of malignant melanoma is not inuenced by smoking habits.26 Long-term smoking may even lower the risk of developing melanoma, especially acral melanomas.35 The protective effect of smoking on cutaneous melanoma may be related to nicotines precursor function in melanin synthesis, afnity for melanin-containing tissues, irreversible binding to melanin, and accumulation of the tobacco carcinogens NNK and NNN in tissues containing melanin. Interestingly, tobacco constituents have been shown to inhibit UVBinduced skin tumors in hairless mice by blocking the nuclear factor-jB signaling pathway.13 Smoking is associated with a lower risk of classic Kaposis sarcoma (cKS)36 and AIDS-related Kaposis sarcoma.37 However, clinical trials of transdermal nicotine for the treatment of cKS in nonsmokers have not shown to be effective for cKS lesions or HHV-8 levels.38 Tobacco-related carcinogenicity is most notably due to the effects of polycyclic aromatic hydrocarbons, nitrosamines and heterocyclic amines. Smoking has been shown to delay DNA repair of single-strand breaks39 and exert a direct tumor-promoting effect.40 Nicotine is also prooncogenic via increased mitotic activity of basal cells and the appearance of hypertrophic epithelial cells in the epidermis.41 Nicotine and tobacco nitrosamine promote tumor growth by activating and upregulating cellular nAChRs, inducing cancer cell invasion and inhibiting apoptosis.42 Pro-invasive effects of nicotine are mediated by a7 nAChR.43 Nicotine increases acetylcholine secretion, expression, and activity of nAChR in cancer cells.44 Receptor-mediated tobacco toxicity involves cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of keratinocyte a7 nAChR (Fig. 5).45 Nicotine has been shown to stimulate growth of tumors via an increase in phospho-ERK. The proliferative effects of nicotine can be blocked by inhibition of a7 nAChR with the high-afnity ligand, a-cobratoxin.46 Pharmacological blockade of a7 nAChR inhibits tumor growth by induction of apoptosis and decreased expression of vascular endothelial growth factor, inhibiting neoangiogenesis.47
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Figure 5 Cooperation of the Ras/Raf/MEK/ERK and JAK-2/

STAT-3 pathways downstream of keratinocyte a7 nAChR. Stimulation of a7 nAChR by either its physiological ligand acetylcholine (ACh) or nicotine (Nic) leads to alterations in gene expression due to transactivation of STAT-3, which occurs through two complementary signaling pathways coupled by this receptor. The pathway mediated by stepwise activation of Ras/Raf/MEK/ERK provides for an increased cytoplasmic concentration of STAT-3 due to an upregulated expression, whereas activation of the tyrosine kinase JAK-2 provides for phosphorylation of STAT-3 with subsequent translocation of STAT-3 dimers to the nucleus to alter gene expression (with permission from Ref. 45)

skin aging. For instance, reduced collagen production17 and altered extracellular matrix turnover with increased levels of MMP-853 are both reported to contribute to aberrant wound healing. Smoking may also affect wound healing by inhibiting broblast migration into the wound bed, resulting in broblast accumulation at the edge of the wound. An increase in broblast survival along with a decrease in cell migration may lead to brosis and excessive scarring.54 Wound epithelialization, however, is mediated by crawling locomotion of keratinocytes over the denuded dermis. Keratinocyte migration is regulated through both nicotinic and muscarinic classes of acetylcholine receptors and can be inhibited by activation of the a7 nAChR that couples ionic events and protein kinase signaling cascades to regulate sedentary integrin expression and Rho-kinase activity.5558 Smoking can also cause delayed wound healing secondary to decreased blood ow. While smoking attenuates cutaneous blood ow, tissue oxygen, and aerobe metabolism, nicotine alone increases tissue oxygen despite blood ow reduction.59 Therefore, nicotine is unlikely to mediate the vasoactive effect of smoking. Nicotine appears to affect wound healing only when administered in toxic doses. In therapeutic doses, however, transdermal nicotine has been shown to normalize digital microvascular perfusion60 and stimulate wound healing and angiogenesis.61 Treatment with nicotine actually promoted wound healing in mice.62 In addition to upregulating the epithelialization rate, the mechanism might include enhanced synthesis of type I collagen.63 Chronic dermatoses affected by smoking
Contact dermatitis

There are also indirect tumor-promoting effects on cancer cells via endothelial cells and dermal broblasts. Nicotine can enhance tumor growth through an increase in tumor vascularity48 and creation of a pro-carcinogenic stromal environment.49 Exposure to smokeless tobacco extract prompts human dermal broblasts to secrete factors that increase the proliferation and invasiveness of immortalized keratinocytes. Therefore, UV light and tobacco nitrosamines can induce carcinogenesis, whereas nicotine facilitates growth and spreading of transformed cells. Aberrant wound healing Smokers carry a greater complication risk for surgical wounds.50 Animal studies have shown that smoking within eight weeks of surgery increases the risk of skin ap necrosis.51 On the other hand, abstinence from smoking reduces the risk of wound infection.52 The pathobiological effects of tobacco products on wound healing are similar to those eliciting precocious

Cigarette and snuff usage are known risk factors for developing allergic contact dermatitis. In cigarettes, allergens such as cocoa, menthol, licorice, colophony, and formaldehyde can be found in the lter, paper and tobacco.64 Smoking can increase the risk of a positive patch test reaction to nickel in a dose-dependent manner.65 Nicotine patches themselves can cause an allergic or irritant contact dermatitis at the site of application, with nicotine being the main allergen.66
Atopic dermatitis

Although smokers have a signicantly higher serum total IgE level, compared with nonsmokers67 the reports are conicting in regard to the effects of smoking on atopic dermatitis. Smoking has been reported to be an independent risk factor for hand eczema.68 However, other studies showed no association between smoking and atopic dermatitis or hand eczema.69

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increases in a dose-dependent pattern.80 In vivo studies show that mice exposed to smoke develop atrophy of the epidermis, reduced thickness of the subcutaneous tissue, and scarcity of hair follicles. Cellular apoptosis is also seen in the hair bulbs.81 Smoking affects the dermal hair papilla microvasculature and leads to DNA damage of the hair follicle.82 It also causes an imbalance in the follicular protease-antiprotease systems affecting the hair growth cycle. An increase in proinammatory cytokines results in follicular microinammation and brosis.
Pustular dermatoses
Figure 6 PPP, a.k.a. pustular psoriasis (with permission from Ref. 129)

Psoriasis

It is well documented that a signicant positive association between psoriasis and smoking exists as a dose response relationship with the number of cigarettes smoked per day.69 Smoking is an independent risk factor for psoriasis,70 which is higher in men.71 In addition, remission of psoriasis after treatment is shorter among smokers.72
Palmoplantar pustulosis (PPP)

While some reports show a dose-related linear relationship between prevalence and severity of acne vulgaris and cigarette consumption,83 other studies reveal no association.84 In fact, a lower prevalence of acne in smokers has been reported.85 The risk of developing rosacea is also lower among current smokers, perhaps due to the vasoconstrictive effects.86 A strong association has been established between smoking and hidradenitis suppurativa (a.k.a. acne inversa).87 A causative role of the nonneuronal cholinergic system in the pathogenesis of hidradenitis suppurativa has been suggested by the aberrant expression of nAChRs in the lesional skin.88
Immunoblistering dermatoses

PPP (Fig. 6) is one of the most common inammatory skin diseases associated with smoking. Among patients with PPP, 95% are smokers, and the majority are heavy smokers.73 Smoking cessation leads to signicant improvement, with fewer pustules and less erythema and scaling.74 The acrosyringium is a target of inammation in PPP. Patients with PPP may have an abnormal inammatory response to nicotine, because there is an aberrant expression of nAChRs and other components of the cutaneous cholinergic system. These observations suggest a role for nicotine in the pathogenesis of PPP.75
Cutaneous lupus erythematosus

Smoking has been reported to improve pemphigus vulgaris. This is consistent with a lower proportion of smokers among patients with pemphigus.89 Smokers with pemphigus vulgaris achieve partial and complete remission more frequently than nonsmokers.90 An inverse association also exists between tobacco usage and dermatitis herpetiformis and related celiac disease.91 The incidence of endomysial antibody-positive cases among adults recently diagnosed with celiac disease is lower among smokers than nonsmokers.92 However, one study revealed no relationship between smoking and the presence of anti-gliadin antibodies.93 No signicant association has been found between mucous membrane pemphigoid and smoking.94
Skin ulcers

Studies reveal a statistically signicant association between active smoking and development of cutaneous lupus erythematosus.76 An association between discoid lupus erythematosus (DLE) and smoking has also been shown. Smokers with DLE have more extensive involvement at disease onset.77 In addition, treatment efcacy with antimalarial therapy is decreased by smoking.78
Diseases of hair and hair follicles

Smoking is a risk factor for developing pressure ulcers95 and ulcers complicated by infections in patients with diabetes.96 More than 90% of patients with ulceration due to Buergers disease (thromboangiitis obliterans) are smokers. Long periods of disease quiescence are associated with tobacco cessation, whereas recurrence is associated with resumption of tobacco use.97
Viral diseases of the skin

Smoking is associated with premature graying of hair in both men and women, as well as hair loss in men at an earlier onset.79 Androgenetic alopecia worsens with increasing smoking habits, and the early-onset history
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Smoking has been shown to enhance the risk of genital warts in men.98 In marked contrast, the prevalence of
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recurrent herpes labialis is signicantly lower among smokers, especially among pipe smokers.99 This may be due to the ability of tobacco to inhibit viral replication of herpes simplex and signicantly reduce its cytolytic effect.100 Newer evidence, however, shows that nicotine applied through a transdermal patch induces herpes simplex reactivation and viral shedding in latently infected rabbits.101
Other mucocutaneous diseases

A signicant association has been found between smoking and necrobiosis lipoidica diabeticorum.102 Smoking is also positively associated with generalized urticaria.103 Men smoking cigarettes or bidi have a signicantly higher risk for developing arsenic-induced skin lesions compared with nonsmokers.104 On the other hand, there is a signicantly negative correlation between tobacco use and geographic tongue.105 Skin diseases treated with nicotine As discussed above, smoking can exacerbate many diseases, increase carcinogenesis, and has the potential for addiction. Paradoxically, nicotine has been shown to be effective as a monotherapy in many dermatological conditions. While Buergers disease is strongly associated with smoking cigarettes, it has been successfully treated with nicotine chewing gum (Fig. 7).106 Therefore, substances other than nicotine might induce vasoconstriction and exacerbate Buergers disease in cigarette smokers. Smoking cessation is vitally important in the management of Buergers disease, but the use of nicotine may prove to be a valuable treatment option. The therapeutic effect of cigarette smoking on oral and genital aphthosis in Behets disease is well documented.107 Accordingly, cessation of cigarette smoking

activates mucocutaneous symptoms, especially oral aphthous lesions. However, therapy with nicotine leads to regression of aphthous ulcers within days.108 The mechanism of this effect may involve the ability of nicotine to inhibit the release of the proinammatory cytokines IL-6 and IL-8 from keratinocytes and dermal endothelial cells. Cigarette smoke extract also decreases IL-8 release but increases production of vascular endothelial growth factor by human keratinocytes.109 Inammatory bowel disease (IBD) is epidemiologically related to smoking.110 Smoking and/or pure nicotine may impact the mucocutaneous manifestations of IBD like aphthous stomatitis, pyoderma gangrenosum, and erythema nodosum. Most patients with ulcerative colitis are non-smokers or develop their disease after smoking cessation.111 Smoking cessation worsens disease progression of ulcerative colitis and improves upon resumption of smoking. In contrast, patients with Crohns disease experience severe disease with smoking.112 Nicotine appears to be the key mediator of smoking effects on IBD, because its administration through transdermal patches inhibits inammation associated with ulcerative colitis but not with Crohns disease.113 Notably, mice with trinitrobenzene sulfonic acid-induced colitis treated with the a7 nAChR agonist, anabaseine, show less tissue damage compared with untreated mice.114 Nicotine also has been used to treat pyoderma gangrenosum115 and erythema nodosum,116 both of which may be associated with IBD, and non-associated malignant atrophic papulosis (a.k.a. Degos disease),117 Kimuras disease,116 and eosinophilic pustular folliculitis.118 Similar to ulcerative colitis, recurrent aphthous stomatitis (RAS) occurs less frequently in tobacco users.119 Aphthous stomatitis has been reported to are with abrupt cessation of cigarette smoking and improves with

(a)

(b)

Figure 7 Buergers disease treated with nicotine. (a) The left big toe showing a large deep ulcer (1.5 2.0 cm) in a 38-year-old

man who had smoked for 20 years. (b) The ulcer healed 20 days after chewing nicotine gum (2 mg per piece) twice a day. For at least 14 months thereafter, the patients feet remained in good condition, without ulceration or intermittent claudication, using two pieces of nicotine gum a day without any other drugs (with permission from Ref. 106)
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Table 1 Summary of the effects of tobacco/nicotine on the skin

Mucosal and cutaneous signs of tobacco use Smokers Smokers Smokers Smokers comedones face melanosis mustache

Increased incidence and/or exacerbation Compelling evidence: Aberrant wound healing Acne inversa Buergers disease Contact dermatitis

Controversial reports Acne vulgaris Atopic dermatitis BCC Melanoma SCC (except mucocutaneous type)

No relation Mucosal pemphigoid Oral lichen planus

Decreased incidence and/or improvement Compelling evidence: Behc ets disease Classic Kaposi sarcoma Pemphigus vulgaris Anecdotal reports:

Dermatological use of nicotine Behc ets disease Buergers disease Degos disease Eosinophilic pustular folliculitis Erythema nodosum

Smokers nail

Smokers palate Smokers tongue Tobacco pouch keratosis

Cutaneous lupus erythematosus Precocious skin aging Mucocutaneous SCC (lip, oral cavity, anogenital, keratoacanthoma) PPP Psoriasis Anecdotal reports: Arsenic-induced skin lesions Hair loss and grayness Necrobiosis lipoidica diabeticorum Pressure ulcers Urticaria

Dermatitis herpetiformis Geographic tongue Herpes simplex labialis

Kimuras disease Oral lichen planus Pyoderma gangrenosum Recurrent aphthous stomatitis

Pemphigus foliaceus Rosacea Acral melanoma

BCC, basal cell carcinoma; PPP, palmoplantar pustulosis; SCC, squamous cell carcinoma.

smoking resumption. Nicotine replacement therapy markedly lowers the frequency of RAS, suggesting that nicotine is the therapeutic moiety.120 Although published studies do not reveal an association between smoking and oral lichen planus, one case that was resistant to other treatments responded well to nicotine gum.121 Transdermal nicotine has been demonstrated to directly reduce cutaneous inammation.122 Nicotine and other nAChR agonists may exert their anti-inammatory effects by inhibiting lymphocyte proliferation, endocytosis and phagocytosis of dendritic cells, and production of oxygen free radicals, superoxide, and proinammatory cytokines.123 The mechanism of antiinammatory action may also include release of the anti-inammatory cytokines, IL-10 and TGF-b, glucocorticoids, and soluble receptors neutralizing the activity of proinammatory cytokines. Nicotine activates a7 nAChR that modulates inammation in the absence of parasympathetic innervation. This receptor is essential for inhibiting cytokine synthesis by the cholinergic antiinammatory pathway.124 Conversely, absence of a7 nAChR elicits an enhanced proinammatory cytokine response.125
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Conclusions Tobacco and its constituents affect the skin through external and internal exposures. Various skin cells express the nAChR subtypes that affect cell survival and function. Skin changes are mediated by both genomic and nongenomic effects of tobacco toxins and nicotinic agonists. These effects range from accelerating the aging process to mutagenesis. Epidemiological studies have established both positive and negative associations of tobacco usage in distinct skin diseases. Positive associations with a particular disease can lead to improvement from smoking cessation, whereas inverse correlation may lead toward development of a disease-specic treatment with a nicotinic agonist. It is important to distinguish between the effects of tobacco and pure nicotine, as illustrated by the opposite effects of smoking and nicotine in Buergers disease. The anti-inammatory effect of nicotine is mediated, in part, by activation of a7 nAChR. The effects of tobacco products and pure nicotine on the skin are summarized in Table 1. Further studies are warranted to investigate the potential for nicotinergic agents as a new therapeutic modality for certain skin diseases.
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Questions (see answers on page 262) 1. Which compound is not a toxic constituent of the solid phase in tobacco smoke? a. nicotine b. phenol c. hydrogen cyanide d. catechol 2. Which mucosal nding has been associated with smoking? a. central papillary tongue atrophy b. Fordyce granules c. lingua plicata d. white sponge nevus 3. A smokers face characteristically has a. prominent telangiectasia b. an atrophic, greenish appearance c. a glassy appearance d. a plethoric complexion 4. Smoking leads to an imbalance between biosynthesis and degradation of dermal connective tissue proteins by altering synthesis of a. type I and type IV collagens b. type II and type III collagens c. upregulating matrix metalloproteinases d. type I and type III collagens, upregulating matrix metalloproteinases, and increasing the production of elastin 5. True or False. Nicotine alters cell senescence via overproduction of elastin and underexpression of keratinocyte a7 nicotinic acetylcholine receptor. 6. In particular, smoking is associated with an increased risk of developing squamous cell carcinoma of the a. eyelids b. penis c. chest d. buttocks 7. Animal studies show that smoking within ________ of surgery increases the risk of skin ap necrosis. a. 8 h b. 8 days c. 8 weeks d. 8 months 8. Smoking increases the risk of a positive patch test reaction to ________ in a dose-dependent manner. a. nickel b. neomycin c. quaternium-15 d. thimerosal 9. What is the target for inammation in palmoplantar pustulosis? a. straight duct b. acrosyringium
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c. apocrine duct d. keratinocytes 10. Which disease has successfully been treated with nicotine chewing gum? a. palmoplantar pustulosis b. Crohns disease c. Buergers disease d. genital warts References
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61 Jacobi J, Jang JJ, Sundram U, et al. Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice. Am J Pathol 2002; 161: 97104. 62 Morimoto N, Takemoto S, Kawazoe T, Suzuki S. Nicotine at a low concentration promotes wound healing. J Surg Res 2008; 145: 199204. 63 Sorensen LT, Jorgensen LN, Zillmer R, et al. Transdermal nicotine patch enhances type I collagen synthesis in abstinent smokers. Wound Repair Regen 2006; 14: 247251. 64 Glick ZR, Saedi N, Ehrlich A. Allergic contact dermatitis from cigarettes. Dermatitis 2009; 20: 613. 65 Linneberg A, Nielsen NH, Menne T, et al. Smoking might be a risk factor for contact allergy. J Allergy Clin Immunol 2003; 111: 980984. 66 Bircher AJ, Howald H, Rui T. Adverse skin reactions to nicotine in a transdermal therapeutic system. Contact Derm 1991; 25: 230236. 67 Goel N, Singh BP, Arora N, Kumar R. Effect of smoking on atopic predisposition and sensitisation to allergens. Indian J Chest Dis Allied Sci 2008; 50: 329333. 68 Montnemery P, Nihlen U, Lofdahl CG, et al. Prevalence of hand eczema in an adult Swedish population and the relationship to risk occupation and smoking. Acta Derm Venereol 2005; 85: 429432. 69 Bo K, Thoresen M, Dalgard F. Smokers report more psoriasis, but not atopic dermatitis or hand eczema: results from a Norwegian population survey among adults. Dermatology 2008; 216: 4045. 70 Huerta C, Rivero E, Rodriguez LA. Incidence and risk factors for psoriasis in the general population. Arch Dermatol 2007; 143: 15591565. 71 Zhang X, Wang H, Te-Shao H, et al. Frequent use of tobacco and alcohol in Chinese psoriasis patients. Int J Dermatol 2002; 41: 659662. 72 Raychaudhuri SP, Gross J. Psoriasis risk factors: role of lifestyle practices. Cutis 2000; 66: 348352. 73 Akiyama T, Seishima M, Watanabe H, et al. The relationships of onset and exacerbation of pustulosis palmaris et plantaris to smoking and focal infections. J Dermatol 1995; 22: 930934. 74 Michaelsson G, Gustafsson K, Hagforsen E. The psoriasis variant palmoplantar pustulosis can be improved after cessation of smoking. J Am Acad Dermatol 2006; 54: 737738. 75 Hagforsen E. The cutaneous non-neuronal cholinergic system and smoking related dermatoses: studies of the psoriasis variant palmoplantar pustulosis. Life Sci 2007; 80: 22272234. 76 Boeckler P, Cosnes A, Frances C, et al. Association of cigarette smoking but not alcohol consumption with cutaneous lupus erythematosus. Arch Dermatol 2009; 145: 10121016. 77 Gallego H, Crutcheld CE III, Lewis EJ, Gallego HJ. Report of an association between discoid lupus erythematosus and smoking. Cutis 1999; 63: 231234.

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Answers to Questions 1. c. Hydrogen cyanide is a toxic constituent of the gas phase of tobacco smoke. 2. a. Central papillary tongue atrophy has been associated with smoking. 3 d. A smokers face characteristically has prominent wrinkles, a gauntness of facial features with prominence of the underlying bony contours, an atrophic, gray appearance of the skin, and a plethoric complexion. 4. d. Smoking leads to an imbalance between biosynthesis and degradation of dermal connective tissue proteins by altering synthesis of type I and type III collagens, upregulating matrix metalloproteinases, and increasing the production of elastin. 5. False. Nicotine alters cell senescence via overproduction of elastin and overexpression of keratinocyte a7 nicotinic acetylcholine receptor. 6. b. Smoking is associated with an increased risk of developing squamous cell carcinoma of the penis, vulva, cervix and anus. 7. c. Smoking within 8 weeks of surgery increases the risk of skin ap necrosis. 8. a. Smoking can increase the risk of a positive patch test reaction to nickel in a dose-dependent manner. 9. b. The acrosyringium is the target for inammation in palmoplantar pustulosis. 10. c. While Buergers disease is strongly associated with smoking cigarettes, it has been successfully treated with nicotine chewing gum.

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