Chapter 14 Eczema, psoriasis, skin cancers and other skin disorder
Introduction
The integument (the skin) is the largest and heaviest organ in the human body consisting of approximately 16% of body weight and is the primary interface between the internal environment and the outside surroundings.1 Given that the thickness of skin has an extremely thin foundation, the epidermis protects animals against major environmental stresses, such as water loss and microorganism infection. Hence, the skin’s primary function is to act as a barrier to protect the body from damage caused by outside forces, contaminants, microorganisms and radiation exposure.
The skin epidermis and its appendages undergo ongoing renewal by a process called homeostasis. Stem cells in the epidermis have a crucial role in maintaining tissue homeostasis by providing replacement cells to those that are constantly lost during tissue turnover or following traumatic injury. A number of different skin stem cell pools contribute to the maintenance and repair of the various epidermal tissues of the skin. These include the inter-follicular epidermis, hair follicles and sebaceous glands. It is interesting to note that the basic mechanisms and signalling pathways that orchestrate epithelial morphogenesis in the skin are reused during adult life to regulate skin homeostasis.2
In clinical practice, dermatology includes about 3000 diseases that affect the skin and its accessory tissues (e.g. hair and nails).3 While many infamous epidemics with prominent skin manifestations such as small pox, plague, leprosy, and anthrax, have been largely controlled,4 other dermatologic diseases such as warts, acne, and dermatitis remain especially common.
In 2004, more than 50% (165 million) of the US population suffered from herpes simplex virus (HSV) and herpes zoster virus (HZV) infections, and 83.3 million cases of human papilloma virus (HPV) infection were noted.2 Indeed, at any given time, it has been reported that at least 25% of the population of the US suffer from at least 1 skin disease5,6 — a state that constitutes a significant global burden of disease.2, 7–10 A recent study from the US on the burden of skin diseases demonstrated that skin disease was 1 of the top 15 groups of medical conditions for which prevalence and health care spending increased the most between 1987 and 2000, with approximately 1 in 3 persons diagnosed with a skin disease at any given time (see Table 14.1).
| Skin disease | Prevalence in millions as at 2004 |
|---|---|
| Acne (cystic and vulgaris) | 50.2 |
| Actinic keratosis | 39.5 |
| Atopic dermatitis | 15.2 |
| Benign neoplasms/keloid | 29.4 |
| Bullous diseases | 0.14 |
| Contact dermatitis | 72.3 |
| Cutaneous fungal infections | 29.4 |
| Cutaneous lymphoma | 0.02 |
| Drug eruptions | 2.6 |
| Hair and nail disorders | 70.5 |
| Herpes simplex and zoster | 165.0 |
| Human papillomavirus/warts | 58.5 |
| Lupus erythematosus | 0.36 |
| Psoriasis | 3.1 |
| Rosacea | 14.7 |
| Seborrheic dermatitis | 5.9 |
| Seborrheic keratosis | 83.8 |
| Skin cancer— melanoma | 0.72 |
| Skin cancer— non-melanocytic | 1.2 |
| Skin ulcers and wounds | 4.8 |
| Solar-radiation damage | 123.1 |
| Vitiligo | 1.5 |
(Source: adapted and modified from Bickers et al. 2006)11
Exposure of the skin to UV light has the potential to induce the formation of high concentrations of reactive oxygen species (ROS) which can destabilise ROS signalling functions and damage organelles and modify the structures of important molecules such as proteins, lipids and genetic material.12 Sunlight, particularly ultraviolet B (UVB) (wavelength 290–320 nm), is responsible for sunburn, but also causes cellular damage. UVA light (wavelength 320–400 nm) burns less than UVB (wavelength 290–320 nm) and penetrates deep into the dermis (as far as the boundary with the epidermis). UVA light makes up the majority of sunlight, and is absorbed by a wide range of molecules, which can become photosensitisers, and can do more damage to the skin due to its greater ability to penetrate. Environmental pollutants such as ozone and oxides of nitrogen and sulphur are also able to produce free radicals in the skin, thereby also risking skin damage.13 Although formed in the outer layers of the epidermis, these radicals induce damage in deeper layers in a manner similar to UV light.
A number of nutraceuticals have been claimed to exhibit useful activities in the area of skin health, including proanthocyanidins and the pine bark extract Pycnogenol, carotenoids, polyunsaturated fatty acids (PUFAs), tea, soy, glucosamine and melatonin.14
Lifestyle factors
Smoking
The adverse health risks associated with smoking are well documented and this is also important for overall skin health. Smoking has been associated with the positive and negative prevalence of numerous diseases and conditions of the skin (see Table 14.2).15, 16
Epidemiological studies have demonstrated that tobacco smoking is one of many factors that significantly contributes to premature skin ageing in addition to other factors such as age, sex, skin pigmentation, sun exposure history, and alcohol consumption.17–20 Moreover, smoking is the causal factor of smoker’s wrinkles. Similarly, as with chronic exposure of the skin to ultraviolet radiation, tobacco also promotes manifested alterations in the structure and composition of the epidermis and dermis, similarly to that observed with photo-ageing. 21, 22, 23 In a recent study, tobacco smoking, but not ultraviolet exposure, was determined to be a strong predictor of skin ageing.24
Although smoking may have certain beneficial effects on some skin diseases (as described in Table 14.2), it is exceptionally difficult to favour this habit which is highly damaging to overall health. Tobacco smoking is currently the leading preventable cause of disease and death in Western countries, and some of its beneficial effects on the skin are significantly dwarfed when compared to the hazard risks to health encountered with habitual tobacco use for both smokers and those who are exposed to secondary tobacco smoke, therefore it cannot be recommended.
Alcohol
The long-term consumption of alcohol in excessive quantities can damage every organ system in the body. A recent report has documented that chronic excessive alcohol consumption in alcoholics was associated with a wide range of skin disorders that included urticaria, porphyria cutanea tarda, flushing, cutaneous stigmata of cirrhosis, psoriasis, pruritus, seborrheic dermatitis and rosacea.25
Life stressors
Psycho-emotional stressors have long been expected to exacerbate or even trigger allergic diseases such as atopic dermatitis (see Figure 14.1).26, 27
Psychodermatological or psychocutaneous disorders are conditions resulting from the interaction between the mind and the skin. There are 3 major groups of psychodermatological disorders recognised; psychophysiologic disorders, psychiatric disorders with dermatologic symptoms, and dermatologic disorders with psychiatric symptoms.28
A number of human studies have reported associations between personality traits and psychic disturbances such as stress perception, anxiety, or depression and atopic dermatitis severity or even onset.29–32
The nature of the mechanisms that link stress and exacerbation of skin inflammation remain largely unknown. Recent studies suggest psycho–neuro–immunologic factors and emotional stressors are important in its evolution (Figure 14.1).33
The established explanation is that immune balance is altered by activation of 2 stress axes; namely, activation of the hypothalamic–pituitary–adrenal (HPA) axis that raises cortisol levels, and activation of the sympathetic nervous systems which raises adrenaline levels (Figure 14.1).34 This mechanism of activity has been further investigated in wound-healing experiments. For more than a decade it has been extant that stress/stressors (which can range in magnitude and duration) can significantly slow wound healing.35, 36
Itch is a major feature of many skin diseases, which adversely affects patient’s quality of life. Recently it was shown that cognitive factors, such as helplessness and worrying, and the behavioural response of scratching were indicated as possible worsening factors. This is consistent with overall findings that implicate a biopsychosocial model for the itch sensation.37
Sunlight/ultraviolet (UV) exposure
Acute adverse effects of sun exposure
Acute overexposure to sunlight causes sunburn, primarily because of ultraviolet B (UVB) (290–320 nm) radiation. This is characterised by erythema, oedema, and tenderness. Sunburn represents injury to both epidermal and dermal layers.38
Lentigo maligna
Repeated acute exposure over time may enhance the risk of skin disease as reported in a recent epidemiological study. The study reported that although chronically sun-exposed skin was recognised as a prerequisite for lentigo maligna, the risk of lentigo maligna did not increase with the cumulative dose of sun exposure; however, that lentigo maligna was associated with sunburn history, like all other types of melanomas. The main epidemiological characteristic of lentigo maligna reported in this study was the absence of an apparent relation with the genetic propensity to develop nevi.39
Skin cancers
The influence of painful sunburns and lifetime sun exposure to the skin has also been studied in other skin diseases.40 Lifetime sun exposure was predominantly associated with an increased risk of squamous cell carcinoma (SCC) and actinic keratoses and to a lesser degree with basal cell carcinoma (BCC). By contrast, lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma, despite the fact that lifetime sun exposure did not diminish the number of melanocytic nevi or atypical nevi. Neither painful sunburns nor lifetime sun exposure were associated with an increased risk of seborrheic warts.
Chronic adverse effects of sun exposure
Carcinogenesis
Over 100 years ago, Paul Gerson Unna correctly identified chronic solar exposure as the cause of SCC.41 The vast majority of the non-melanoma forms of skin cancer (SCC and BCC) result from chronic or intense intermittent solar exposure, and perhaps two-thirds of melanoma worldwide have solar UV radiation (UVR) as an aetiological causal factor.42
The 3 types of skin cancer are: basal cell carcinoma (BCC), squamous cell carcinoma (SCC); and melanoma.43 (See also Chapter 9.)
Photo-ageing
Photo-ageing is a multisystem degenerative process that involves the skin and its support system. Photo-ageing results from repeated sun exposure rather than to those changes resulting from the passage of time alone.44
Avoiding over-exposure of the skin to the sun can beneficially promote smooth, unblemished skin even in the ninth decade of life, showing only laxity and deepening of the expression lines. Photo-aged skin displays a telangiectatic, leathery, dry, coarse, nodular yellowish surface, with deep wrinkles, accentuated skin furrows, mottled pigmentation, and purpura, as well as a variety of benign, premalignant, and malignant neoplasms. Lifetime sun exposure is also positively associated with xerosis, spider angioma, and superficial varicose veins.45
Contact allergy and the skin
Contact allergy caused by ingredients in cosmetic products is a well-known problem (see Table 14.3). In the US it has been reported that approximately 6% of the general population has a cosmetic-related contact allergy, mainly caused by constituent compounds such as preservatives or fragrances in the cosmetic product.46–49
Table 14.3 Important allergens for consideration in cosmetics
| Allergen | Function |
|---|---|
| Amerchol™ L101 | Emulsifier |
| p-Aminobenzoic acid | Sunscreens |
| Balsam of Peru (Myroxylon pereirae) | Fragrance |
| Benzophenone 3 | Sunscreens |
| 2–Bromo–2–nitropropane–1,3–diol (Bronopol) | Preservative |
| Butylated hydroxyanisole | Antioxidant |
| Butylated hydroxytoluene | Antioxidant |
| Cetyl/stearyl alcohol | Emulsifier |
| Cocamidopropyl betaine | Surfactant |
| DMDM hydantoin |
(Source: data adapted and modified from Ortis, Yiannias49 and Orton, Wilkinson)50
Mind–body medicine
The endocrine system serves as a central gateway for psychologic influences on health. Stress and depression can cause the release of pituitary and adrenal hormones that have multiple effects on immune function that can subsequently influence skin physiology. Furthermore, skin problems associated with depression and or anxiety can be classified accurately as psychophysiologic disorders. They can be elicited and worsened by psychologic factors and, in turn, living with them can be associated with a higher prevalence of emotional disorders, such as depression and anxiety.51 Hence, there is a brain–skin connection via psychoneuroimmunological–endocrine mechanisms that, through human behaviours, can strongly influence the initiation and exacerbation of skin disorders.
Cognitive behavioural therapy (CBT)
It has been reported that CBTs deal with dysfunctional thought patterns (cognitive) or actions (behavioural) that can damage the skin or can interfere with dermatologic therapies.52 CBT-responsive skin disorders include:
The mechanism by which hypnosis produces improvement in symptoms and in skin lesions is not completely understood. Hypnosis may help regulate blood flow and other autonomic functions not usually under conscious control. The relaxation response that accompanies hypnosis may alter neurohormonal systems that in turn regulate many body functions.53
Biofeedback
Instrumentation that can measure galvanic skin resistance, skin temperature, or other manifestations of autonomic nervous system activity in the skin and then display it in a visual, auditory, or kinesthetic mode gives the individual sensory biofeedback. With training, individuals may learn consciously how to alter autonomic nervous system associated responses for skin problems, and with enough repetition may establish new habit patterns.56
Early reports show that biofeedback of galvanic skin resistance for hyperhidrosis and biofeedback of skin temperature for dyshidrosis and Raynaud’s syndrome can be effective.57, 58 When biofeedback was combined with hypnosis the efficacy was reported to be enhanced.
Psychological/educational interventions
Atopic eczema
Psychological and educational interventions have been incorporated as adjuncts to conventional therapies for children with atopic eczema. These interventions enhance the effectiveness of topical therapy. A recent systematic review has reported that there is a lack of rigorously designed trials (that excluded a recent German study) that provided only a limited amount of evidence of the effectiveness of psychological and educational interventions in assisting to manage atopic eczema in children.59
There is low-level evidence for the use of affirmations, prayer and meditation in ameliorating skin disorders and further studies are required because it has been long recognised that there is a significant link between stress and the development of skin disorders.60
Physical activity
Furthermore, there are numerous studies that have investigated the beneficial effects of physical activity, tai chi and yoga for the management of stress61–65 and it is biologically plausible to conclude that providing advice to patients about the benefits of physical activity, tai chi and yoga may also be favourable options for the management of stress that could indirectly also assist with skin conditions.
Nutrition and the skin
Treatment regimens have their origins from numerous areas that are diversely derived from complementary medicine techniques, historical use and traditional healing systems such as Ayurveda, and the systems fashioned by various empirical nutritional therapists.66
As is well known, diet has been recognised to be important in the treatment of several disorders. For example, stimulants and hot foods have been related to acne rosacea,67 wheat gluten to dermatitis herpetiformis,68 and zinc deficiency to acrodermatitis enteropathica.69 Other nutritional deficiencies have historically been recognised to play a role in dermatitis, such as in vitamin B1 deficiency that leads to pellagra.70
Food sensitivities
Population-based assessments of food allergy are scarce.71 Despite the difficulties in obtaining firm population-based data on the prevalence of food allergies, there has been evidence for a general increase in food allergies, documented best for peanut, sesame, and kiwi, that could be attributed to environmental and dietary factors including reduced immune stimulation from infection; that is, the hygiene hypothesis. There have been changes in the components of the diet, including antioxidants, fats, and nutrients such as vitamin D, as well as the use of medications.72, 73, 74
Addressing food allergies (food sensitivities), is an important nutritional elimination procedure. These are reactions to foods that are far broader than the classical reactions such as urticaria, itchy eyes, and rhinitis. They include any inflammatory manifestation as well as a variety of neurological and other non-inflammatory conditions.75
Food hypersensitivity can be the first stage in the development of allergic diseases, such as atopic eczema.76 It has been reported that clinicians have found that elimination of specific foods found by food challenge to elicit symptoms can lead to significant improvement in eczematous symptoms.77 There is a vast amount of scientific literature claiming that dietary elimination causes improvement of atopic eczema in some cases. However, a recent systematic review portrays the evidence available as weak and the issue of exclusion diets in atopic eczema remains contentious.78
Diets
The eradication from the diet of chemicals is an effective way to eliminate potential skin diseases that are aggravated by chemicals. The Palaeolithic diet has addressed such issues in the scientific/medical literature.79 The essential of this diet involves the consumption of those foods that have a low glycemic index (GI) and consists of meat, fish, vegetable, fruit, roots, and nut consumption and excludes grains, legumes, dairy products, salt, refined sugar, and processed oils. Adherence to this diet in turn minimises the consumption of pesticides, petroleum-based fertilisers, preservatives, artificial flavourings, and artificial food colours.
Acne vulgaris
Studies have reported that excessive intake of refined carbohydrates might contribute to the high rates of acne seen in Western countries through a mechanism involving insulin-stimulated androgen production and that hence nutrition-related lifestyle factors play a role in the pathogenesis of acne and that adhering to a diet with low GI foods improves skin health.80, 81, 82 A recent Cochrane review has reported that improving lifestyle eating profiles such as adhering to a low-GI dietary regimen can improve health outcomes,83 which could in turn improve skin health. The systematic review reported that overweight or obese people on a low-GI diet lost more weight and had more improvement in lipid profiles than those receiving carbohydrate diets. Body mass, total fat mass, body mass index (BMI), total cholesterol and LDL cholesterol all decreased significantly more in the low GI group. In studies that compared ad libitum low-GI diets to conventional restricted energy low-fat diets, participants fared as well or better on the low-GI diet, even though they could eat as much as desired. Therefore, this review concluded that lowering the glycaemic load of the diet appears to be an effective method of promoting weight loss and improving lipid profiles and can be simply incorporated into a person’s everyday lifestyle. This improvement may well extend to include better skin health. A recent study further emphasises that there could be a possible role of desaturase enzymes in sebaceous lipogenesis and the clinical manifestation of acne.84
Nutritional supplements
Beneficial effects have been demonstrated in various experimental model systems including topical application of these ingredients. Recently, oral supplements containing various dietary bioactive molecules have also been reported to be beneficial for skin.87
Vitamins
Vitamin A and analogues
Vitamin A includes all naturally occurring, nutritionally active forms of vitamin A (i.e. retinol, retinyl esters) and the carotenoids. Retinoids include natural metabolic products and synthetic analogues of vitamin A. Vitamin A is physiologically essential for the reproductive system, bone formation, vision, and epithelial tissues. Cutaneous signs of its deficiency include xerosis and phrynoderma. Beta-carotene is a precursor to vitamin A, and is a putative antioxidant, that can protect cell membranes from lipid peroxidation and plants from UV light-induced damage. Retinoids have long historical therapeutic uses since the first introduction of topical tretinoin (retinoid) for the treatment of acne vulgaris.88 An early study demonstrated that orally administered vitamin A to benefit acne when used in high doses (300,000 units per day for women, 400,000 to 500,000 units daily for men) with adverse events reported limited to xerosis and cheilitis.89
There have been approximately 2500 new retinoid compounds synthesized.90 Vitamin A stimulates various aspects of wound repair. It affects fibroplasia, collagen synthesis, epithelialisation, and angiogenesis and is involved in inflammatory processes with specific effects on macrophages, which play a dominant role in wound healing.91
Retinoids already approved for the treatment of dermatological conditions include:
The treatment of disorders of abnormal keratinisation, such as Darier’s disease and Kyrle’s disease, has been ascribed to etretinate and acitretin which are established in Europe for the treatment of Darier’s disease and ichthyosis, especially the nonbullous congenital type.92 In the US, however, these compounds have only been approved by the FDA for psoriasis. Palmoplantar keratoderma also responds well to these drugs, but treatment is justified only in severe cases.93 Pityriasis rubra pilaris has been treated successfully with isotretinoin in the past,94 but now acitretin seems to be the drug of choice in Europe.
It has been reported that retinoids possess certain properties that make them good candidates for cancer prevention and therapy. They are metabolically active compounds that can induce changes in cellular function and appearance, and that can modify the expression of a variety of genes involved in cell growth and differentiation.95
Topical tretinoin, at concentrations of 0.05% and 0.1%, have been used in combination with hydroquinone and corticosteroids for the treatment of melasma.96 Isotretinoin, etretinate, and acitretin have all been used in recalcitrant cases of lichen planus and cutaneous lupus erythematosus with good results.97 Erythropoietic protoporphyria responds to treatment with beta-carotene.
The use of retinoids has been significantly more successful in skin cancer prevention in high-risk patients. Treatment of patients suffering from xeroderma pigmentosum with 2mg/kg/day isotretinoin for 2 years resulted in an average reduction of 63% in the number of skin cancers compared with the 2-year interval before intervention.98
Furthermore, patients with nevoid basal cell carcinoma (BCC) syndrome have been reported to benefit from the same dose of isotretinoin treatment, as there was a rapid decrease in the number of new BCCs.99 Also transplant recipients are also a high-risk group for the development of skin cancer. It has been reported that etretinate at a dose of 50mg/day and acitretin at 30mg/day reduced the incidence of skin cancer in renal transplant recipients.100 An additional group that is appropriate for skin cancer chemo-prevention includes patients with premalignant lesions and a history of 1 or a few skin cancers. Vitamin A (25 000IU per day) appears to benefit patients with many actinic keratoses and a history of fewer than 3 skin cancers101 but not those with 4 or more cancers.102 Albeit retinoids have shown promise as skin cancer chemo-prevention agents, their benefits do not persist after discontinuation of treatments. It should be also noted that long-term use is associated with possible severe side-effects and therefore careful patient monitoring is required.
Researchers have reported favourable responses to isotretinoin and etretinate in patients with multiple keratoacanthomas.103, 104 Other studies with patients with SCC were also reported to be successfully treated with oral isotretinoin.105 However, in most cases responses of advanced skin cancers to retinoids have been largely disappointing.
Vitamin C (Ascorbate)
Ascorbate has a known catalytic role and hence is a co-factor for a number of enzymes. Most cutaneous manifestations of ascorbate deficiency (scurvy) can be attributed to its role as a cofactor for prolyl and lysyl hydroxylase. Ascorbate plays a critical role in wound healing.106
Moreover, ascorbate has the potential to act as a photo-protectant. Skin damage caused by UV radiation includes acute events like sunburn and photosensitivity reactions as well as long-term exposure events that can lead to photo-ageing and skin cancer. It is important to note that ascorbate levels of the skin can be severely depleted after UV irradiation.107
Vitamin C has been reported to protect the skin from UVA-mediated and UVB-mediated phototoxic reactions,108, 109 and when it is combined with a UVA sunscreen, a greater than additive protection is noted. Reduced sunburn reaction, measured by minimal erythema dose and cutaneous blood flow, has also been reported in human studies after systemic administration of 2g vitamin C and 1000IU of vitamin E for 8 days.110 Orally administered vitamin C has been shown to protect mice from UV induced dermal neoplasms. These studies have reported that increases in dietary vitamin C decreased the incidence and delayed the onset of malignant lesions.111, 112
Numerous reviews have consistently reported on studies that have demonstrated that ascorbate can be photo-protective and aid skin repair.113–118
Vitamin E
Vitamin E includes tocopherols and tocotrienols and is a putative antioxidant with no known catalytic roles. However, given that it is a fat soluble (lipophilic) vitamin, it may have important intracellular metabolism modifying functions.118
Skin damage, UV radiation
Research has demonstrated that topically applied alpha-tocopherol can inhibit thymine dimer formation after UVB irradiation in a dose-dependent manner, providing a mechanism through which vitamin E can prevent gene mutations and thus development of skin cancer.119 Vitamin E hence, can be topically applied to skin protecting it from UV-induced damage.
Topical application to the skin of laboratory animals (mice), with vitamin E, has demonstrated a significant benefit immediately after UVB exposure to reduce sunburn-associated erythema, oedema, and skin sensitivity.120 Also chronic photo-damage, assessed by skin wrinkling and tumour development, has also been shown to be delayed by topical application of 5% tocopherol before UVB exposure.121 The efficacy in humans is contentious.
In contrast, a study by Werninghaus and colleagues122 has reported that daily supplementation of healthy individuals with 400IU of natural-source vitamin E for up to 6 months did not significantly alter UV-induced skin damage, as assessed by minimal erythema dose and sunburn cell formation.
A recent review123 has cited numerous topical studies (laboratory animal and human studies) that have demonstrated that vitamin E application prior to UV exposure significantly reduced:
Early uncontrolled trials, using topical application of vitamin E have demonstrated relief of pain and aided in the healing of oral herpetic lesions (gingivostomatitis or herpetic cold sores). In 2 studies, the affected area was dried and cotton saturated with vitamin E oil (20 000–28 000IU per ounce) was spread over the lesions for 15 minutes.124, 125 Pain relief was noted within 15 minutes to 8 hours, and the lesions regressed more rapidly than normal. In some cases, a single application was beneficial, but large or multiple lesions responded better when treated 3 times daily for 3 days. In a further study of 50 patients with herpetic cold sores, the content of a vitamin E capsule was applied to the lesions every 4 hours. The results of this study126 demonstrated prompt and sustained relief of pain and the lesions healed more rapidly than was otherwise expected.
Vitamin D
Psoriasis
Chronic plaque psoriasis is the most common type of psoriasis and is characterised by redness, thickness and scaling. A recent systematic review that investigated the efficacy of cortecosteroid medication and vitamin D on chronic plaque psoriasis has concluded that dithranol and tazarotene performed better than placebo and that comparisons of vitamin D against potent or very potent corticosteroids found no significant differences. However, combined treatment with vitamin D/corticosteroid performed significantly better than either vitamin D alone or corticosteroid alone.127
Calcipotriol, a vitamin D analogue (and a synthetic derivative of calcitriol), has been reported in a randomised controlled trial (RCT) of supervised treatment of psoriasis in a day-care setting can be considered as a first-line approach in clinical practice.128 Patients who participated in this multi-centre clinical trial were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. The study concluded that topical treatment in combination with interventions explicitly focusing on improvement of coping behaviour and psychosocial functioning may further increase the degree of improvement in the psychosocial domains of quality of life in this patient group.
Recently a clinical trial reported that calcitriol ointment at a concentration of 3μ/g was a safe, effective, and well-tolerated option for the long-term treatment of chronic plaque psoriasis. Clinical improvement was maintained for up to 52 weeks, with no clinical effect on calcium homeostasis or other relevant laboratory test parameters observed.129
Atopic dermatitis
In a recent double-blinded randomly assigned pilot study participants took ergocalciferol 1000IU or an identical-looking placebo once daily for 1 month for winter-related atopic dermatitis in children.130 Four out of the 5 child participants who received vitamin D compared with 1 out of the 5 who received placebo had a documented improvement but the difference was not statistically significant when the differences between baselines for the 2 groups were calculated. A study with larger participant numbers is required. The role of vitamin D in inflammatory skin diseases such as atopic dermatitis in children remains to be elucidated. Recently the American Academy of Paediatrics in the US recommended an increase to the daily dose of vitamin D in children from 200 to 400IU per day.131 Noticeable effects, on the incidence of atopic dermatitis hence remain to be reported.
Skin cancers and malignant melanomas
New scientific findings convincingly demonstrate that Vitamin D deficiency is associated with a variety of severe diseases including various types of cancer.132 Hence sun exposure has been reported from various locations 133–136 to be associated with a relatively favourable prognosis and increased survival rate in various malignancies, including malignant melanoma. A recent meta-analysis concluded that there is a growing body of evidence that Vitamin D may be of significant importance for the pathogenesis of cutaneous malignant melanoma.137
B Group Vitamins
Sporadic studies have been reported in the scientific literature which investigated the topical application of specific B group vitamins to the skin. Topical nicotinamide, the physiologically active form of niacin, was reported to have efficacy comparable to that of topical clindamycin in the treatment of acne vulgaris138 and has produced good results in patients with necrobiosis lipoidica.139 In combination with tetracycline, nicotinamide was successful in 1 patient with dermatitis herpetiformis.140 The combination of nicotinamide and tetracycline has also been proposed as an alternative to systemic steroids in the treatment of bullous pemphigoid.141 The success of nicotinamide in the treatment of these skin disorders perhaps is attributable to a re-regulation of the inflammatory state of the skin.
Other B-complex vitamins that have been used in the treatment of skin disorders include pyridoxine, for the management of erythropoietic protoporphyria,142 and vitamin B12, in combination with folic acid, for the treatment of vitiligo.143
Minerals
Zinc
Zinc is an essential component of many metallo-enzymes involved in cell activities such as protein synthesis DNA and RNA replication, and cell division and it is crucial for the normal development of the skin.144
Acne volgaris
Studies detecting low serum zinc levels in patients with acne have a long history.145,146 The finding that zinc was bacteriostatic against Propionibacterium acnes, inhibited chemotaxis, and could decrease tumour necrosis factor-alpha production provided evidence of its usefulness. Subsequently numerous studies have demonstrated that oral zinc was effective in the treatment of severe and inflammatory acne,147–153 more so than it was for mild or moderate acne.154, 155
Gastrointestinal side-effects can be ameliorated somewhat by ingesting zinc directly after meals. One to 2 milligrams of copper supplementation may be recommended with long-term zinc therapy to prevent copper deficiency as zinc decreases the absorption of copper. Oral zinc salt supplementation has been shown to be equally or less effective than oral tetracyclines.156–159
One study, however, showed that oral zinc sulfate had no effect on male patients with moderate acne after 8 weeks of therapy, despite evidence of systemic absorption.160 Limited efficacy and poor patient compliance caused by gastrointestinal side-effects have limited the use of oral zinc for the treatment of acne. Further trials need to be conducted to assess the efficacy and side-effects of lower doses of orally administered zinc.
Selenium
Selenium has a catalytic role, as a component of glutathione peroxidase, in the regulation of oxygen metabolism, particularly in catalysing the breakdown of H2O2. Studies with laboratory animals have implicated selenium deficits in skin cancer tumorigenesis.162 Human studies however have proven controversial.
Cancer studies
Early clinical studies have demonstrated that skin cancer patients in good general health had a significantly lower mean plasma selenium concentration than did controls, and have reported that serum selenium is predictive of future skin cancer risk in humans.163, 164 A multicenter RCT from the Nutritional Prevention of Cancer Study Group, demonstrated that selenium treatment (200mg) of skin cancer patients for 4.5 years reduced significantly total cancer incidence and mortality and incidences of lung, colorectal, and prostate cancer, but it did not protect against development of another basal or squamous cell carcinoma.
Investigators emphasised the need for confirmation of their results before new public health recommendations regarding selenium supplementation could be made.165
A recent Cochrane review has confirmed this notion.166
In a recent study on the effect of selenium intake on the prevention of cutaneous epithelial lesions in organ transplant recipients it was reported that selenium (at a dose of 200 μg/day) did not prevent the occurrence of skin lesions linked to HPV.167
Recent zinc/selenium trace element supplementation studies have demonstrated significant associations with higher circulating plasma and skin tissue contents of zinc/selenium and improved antioxidant status. These physiological changes were associated with improved clinical outcome, including fewer pulmonary infections and better wound healing.168, 169
Other nutritional supplements
Alpha-hydroxy acids (AHAs)
Acne vulgaris
Studies have demonstrated that AHAs are safe and efficacious, in combination, such as in glycolic acid/retinaldehyde preparations,170, 171, 172 as well as its ability to accompany common topical anti-acne therapies. Also, this combination has been reported to prevent and repair post-inflammatory hyper-pigmented skin that was associated with acne.173 Retinaldehyde, a precursor of retinoic acid, has shown de-pigmenting activity whereas glycolic acid decreases excessive pigmentation by a wounding and re-epithelization process. There appears to be a synergistic effect when these 2 compounds are used in combination.
An early double-blind clinical trial on 150 patients to evaluate the efficacy and skin tolerance of the alpha hydroxy acid gluconolactone 14% in solution (Nuvoderm lotion) in the treatment of mild to moderate acne was compared to its vehicle (placebo) and 5% benzoyl peroxide lotion. The results of the study demonstrated that both gluconolactone and benzoyl peroxide had a significant effect in improving patients’ acne by reducing the number of lesions (i.e. inflamed and non-inflamed). Furthermore, fewer side-effects were reported by patients treated with gluconolactone when compared with benzoyl peroxide.174 Irritation was the main adverse effect when gluconolactone was in high concentrations.
Salicylic acid
Salicylic acid is a phytohormone, a plant product that acts like a hormone by regulating cell growth and differentiation. It is a beta hydroxy acid that is chemically similar to the active component of aspirin. It functions as a topical desquamating agent, dissolving the intercellular cement holding the cells of the stratum corneum together. It is used as a topical keratolytic agent.
Hyperpigmentation
A recent small study of 10 participants with Fitzpatrick skin phototypes IV to VI were randomised to receive two 20% salicylic acid peels followed by three 30% salicylic acid peels to half of the face. The contralateral half of the face remained untreated.175 The results of this study demonstrated that salicylic acid peels were safe in this population of adults. Measured quality of life improved nominally.
Acne vulgaris
In an RCT study, 80 participants with mild to moderate facial acne were randomised to receive either a lipophillic derivative of salicylic acid formulation twice a day or 5% benzoyl peroxide once a day for 12 weeks. The study compared efficacy and tolerance between the treatments for facial acne vulgaris and reported that the lipophillic derivative of salicylic acid formulation could be a treatment option to consider in mild to moderate acne vulgaris patients that are intolerant to benzoyl peroxide.176
Coenzyme Q10 (CoQ10)
CoQ10 is ubiquitous in human tissues, although its level is variable. The level of CoQ10 is highest in organs with high rates of metabolism such as the heart, kidney and liver.177 Compounds such as coenzyme Q10 have been reported to play an increasing beneficial role in skin care. The benefits range from skin conditions such as acne and psoriasis to protection against environmental insults.178
Psoriasis
A recent study that evaluated the clinical effects of supplementation with antioxidants to patients with severe erythrodermic and arthropathic forms of psoriasis reported that co-supplementation with antioxidants such as vitamin E, and selenium plus CoQ10 could be feasible for the management of patients with severe forms of psoriasis.179
The use of CoQ10 has also been heavily promoted for use in cosmeceutical products as a beneficial agent for ageing skin.180, 181
Lipoic acid
Low molecular weight compounds such as lipoic acid have also been reported to be protective low molecular weight antioxidants through a diet rich in fruits and vegetables or by direct topical application for photo-damaged skin.182 However, studies investigating the efficacy of lipoic acid in treating photo-damaged skin are lacking.
Functional foods
Probiotics
A recent review has documented the numerous experimental studies that have found that probiotics exert specific effects in the intestinal lumen and on epithelial cells and immune cells with anti-allergic potential.183 The review also documented that the barrier function and the innate immune system of the skin indicates that the skin’s microbiota have a beneficial role, much like that observed with the gut microflora.184
Atopic dermatitis
Studies worldwide have shown that an environment rich in microbes in early life reduces the subsequent risk of developing allergic diseases such as atopic dermatitis.185 Continuous stimulation of the immune system by environmental saprophytes via the skin, respiratory tract and gut appears to be necessary for activation of the regulatory network including regulatory T-cells and dendritic cells. Substantial evidence now shows that the balance between allergy and tolerance is dependent on regulatory T-cells. Tolerance induced by allergen-specific regulatory T-cells appears to be the normal immunological response to allergens in non-atopic healthy individuals. Healthy subjects have an intact functional allergen-specific regulatory T-cells response, which in allergic subjects is impaired. Evidence on this exists with respect to atopic dermatitis, contact dermatitis, allergic rhinitis and asthma.
In a large meta-analysis of the current literature regarding the use of prenatal and postnatal probiotics for the prevention and treatment or either of atopic dermatitis, Lee and colleagues have reviewed and analysed the data from 10 studies.186
