Disorders of the skin.
Managing skin disorders, such as atopic dermatitis (eczema) and psoriasis, has changed in recent years from mainly symptom control to a focus on disease modification. This change is due to better understanding of the molecular mechanisms underlying barrier functions and immune responses in the skin.
Therapy for adults and children suffering from skin conditions is often complex and time-consuming. Nurses are the key health professionals supporting these families. As our understanding of the causes of these conditions increases, we are better able to educate and support patients to accept and manage their therapy.
Historically, the skin was seen as a largely passive barrier, separating the body's internal environment from the inhospitable outside world, allowing our bodies to maintain moist, warm conditions for the benefit of their cells. Modern science has shown the skin is much more--it is a complex organ, with significant effects on bodily function, especially immunity, and is more involved in health and disease than we yet fully understand.
The skin is one of the body's largest organs and is the most subject to insults from the external environment. Key functions of the skin are: (1)
* Regulation of body temperature.
* Regulation of water and electrolyte content.
* Defence against physical, chemical and radiation insults.
* Front-line immunological defence.
* Synthesis of vitamins and hormones.
Disruption to the skin's essential barrier function results in inflammatory conditions that have far-reaching consequences, both physically and for a person's emotional well-being. Skin diseases can be initiated by disruptions to the barrier function, by impaired skin immune function, or by a combination of these (see Figure 1, p21). Atopic dermatitis (also called eczema) and psoriasis are common chronic inflammatory skin conditions.
Globally, psoriasis prevalence ranges from 0 to 2.1 per cent in children, and 0.9 to 8.5 per cent in adults, and is most common in countries more distant from the equator. (2) Prevalence of atopic dermatitis (AD) in children ranges from less than two per cent (in China and Iran) to about 20 percent in New Zealand, Australia, the United Kingdom and Scandinavian AD prevalence in young children (six to seven years) is increasing in developing nations but appears to have plateaued in Australasia and Europe. (3)
Both AD and psoriasis, along with other skin conditions that result in chronic inflammation, place a large burden on health-care systems worldwide. The burden on children and adults who experience these conditions (and their caregivers) is also huge--physical distress, disturbed sleep, impaired quality of life, and the time and materials involved in managing these conditions bring significant social, employment and financial costs. Psoriasis is also associated with increased risk of cardiovascular disease, depression and psoriatic arthritis. (2) AD often heralds, or is accompanied by, other atopic conditions, such as asthma, allergies and allergic rhinitis. (4)
Managing chronic inflammatory skin conditions relies on topical therapies that alleviate symptoms, and both topical and systemic medications that produce non-specific suppression of immune function. However, with increased understanding of the complex interplay of genetic and immunological factors underlying these conditions, highly targeted therapies are being developed. These offer greater success in managing skin disorders, while providing further insights into their pathophysiologies. (5)
Nurses' support for people with chronic skin conditions is essential in ensuring successful management. (6,7) To provide best care for these patients, nurses must stay up-to-date with the latest understanding of the role of skin in the body's immune function and the complex events underlying development of chronic inflammatory skin disorders.
The skin is broadly divided into three layers: epidermis, dermis and subcutaneous fat. Each of these provides specialised cells and structures, which contribute to the function of the skin.
Keratinocytes are the main cells found in the epidermis. These undergo progressive differentiation as they move from the basal layer (where cell division occurs) up though the spiny and granular layers and into the stratum corneum, where they lose their nuclei and form the outermost layer of the skin. Cells throughout these layers are tightly connected via specialised proteins that form tight junctions (between cells) and desmosomes (attaching cells to the layers below). (1)
The stratum corneum arises where keratinocytes lose their nuclei, flatten and become filled with keratin filaments that are highly organised and held in place by the protein filaggrin. The cells also acquire two envelopes--one formed of proteins and the other of layers of lipids. Between the cells is a further layer of lipids that forms a hydrophobic (water-repelling) environment. (8) The most common lipids in the stratum corneum are ceramides, cholesterol and free fatty acids. (8)
The stratum corneum is the main skin layer providing protection against friction from outside contact and preventing transepidermal water loss (TEWL). TEWL is determined both by the barrier function of the skin and blood flow to the region. It can be used to assess the function of the inside-to-out barrier but may not be a good indicator of the outside-in barrier function. Penetration of the skin barrier from the outside environment is an important consideration when discussing inflammatory skin conditions.
Keratinocytes in the spiny and granular layers are essential to the innate immune function of the skin. Invading pathogens trigger receptors on keratinocytes, causing the rapid release of inflammatory cytokines that signal neighbouring keratinocytes and more distant immune cells. (1) Keratinocytes will also produce antimicrobial peptides (AMPs) that destroy bacteria by piercing their membranes. People with AD have decreased AMP production in the epidermis and are subject to frequent infections; by contrast, psoriasis patients have increased AMP concentration and skin infections are less common. (1,9)
Other cells found in the epidermis include Merkel cells, which are essential for detecting light touch and allow discrimination of shape and texture. (1) Hair follicles, and sweat and sebaceous glands are considered epidermal structures, even though they extend down into the dermis and subcutaneous fat layers. The role of melanocytes is described in Box 1 (see p23).
Also found within the epidermis are Langerhans cells. These are dendritic cells (DCs) performing the same immune function as those found in the gut and airways. DCs are an essential link between innate and acquired immunity. They capture invading pathogens and present the antigenic components to T-lymphocytes, activating the acquired immune pathway. This includes the production of antibodies by B-lymphocytes and the generation of memory cells that patrol the tissues ready to respond rapidly on subsequent encounters with the same pathogen.
Immune functions of the skin are augmented by the presence of symbiotic micro-organisms (including bacteria, fungi, viruses and even mites) nestled in the epidermis and occupying hair and gland shafts. (10)
Skin is not sterile, and plays host to a vast population of bacteria ([10.sup.12] bacteria per square metre of skin) and other micro-organisms--this population is known as the microbiome. The number and species of bacteria depends on the site, number of hair follicles and glands, temperature, sebum (oil) and moisture at the skin surface. The acidic pH of the skin surface means certain species of bacteria are more likely to thrive, while others are unable to establish colonies. Most common bacterial species found on the skin are Staphylococcus (S), Propionibacterium and Corynebactenum. These normal skin residents interact with each other, with our skin cells and with potentially pathogenic micro-organisms to provide protection and to regulate immune function, so the balance between effective and damaging immune responses is maintained. For example, 5. epidermidis is a common skin bacterial species which has been found to act in synergy with AMPs from keratinocytes to prevent colonisation by pathogenic S. aureus. (10)
The type and number of micro-organisms growing on the skin varies with age, sex (due to anatomical differences and differences in sebum, sweat and hormone production), and environmental factors. Occupation, type of clothing, climate and use of soaps, shampoos etc, also affect the skin microbiome. Use of antibiotics is known to affect gut flora, but its impact on skin microbiota is not yet known. (10)
Keratinocytes constantly sample the microbiota and are capable of distinguishing between pathogens and harmless micro-organisms. This may be due to desensitisation through prolonged exposure to the harmless organisms. (10) Disruption to the microbiota, or in the immune response to it, may lie at the root of some inflammatory skin disorders. For example, 90 per cent of people with AD have skin colonised with 5. aureus, compared with fewer than five per cent of those without AD. This suggests some disruption in the natural bacterial population of the skin, but whether this is cause or effect of AD is difficult to determine. (10) In contrast, people with chronic wounds are frequently found to be colonised with the normal skin microbiota, but which have become pathogenic in the wound environment, triggering chronic inflammation and contributing to delayed healing. (10)
The layer underneath the epidermis is called the dermis, which consists of connective tissue interspersed with blood vessels, nerves and a variety of cells. The dermis is divided into two layers plus the basement membrane, which separates the basal keratinocytes from the dermis.
The basement membrane is essential to the structural integrity of the skin. Collagen and other connective tissue fibres ensure the epidermis is strongly anchored to the underlying dermis. Antigens to components of the basement membrane are responsible for the autoimmune conditions of epidermolysis bullosa and pemphigus. (11)
Below the basement membrane is the papillary layer of the dermis. This thin layer is filled with fine blood vessels responsible for supplying oxygen and nutrients to the avascular epidermis, and the removal of waste. The papillary layer of the dermis interdigitates (ie interlocks like the fingers of two clasped hands) with the epidermis via a series of folds called papillae (that are reflected in the ridges seen in the skin lying above them). These increase the area of blood supply by bringing more blood vessels into close contact with epidermal cells. (11)
The reticular layer of the dermis contains carefully arranged bundles of collagen, which provide tensile strength to the skin. The thick elastic fibres give skin its resilience, ie its ability to regain shape when it is deformed. Within these fibres lie a variety of molecules, such as hyaluronic acid, dermatan sulphate and chondroitin sulphate, which absorb and retain water (up to 1000 times their own weight) and control the movement of solutes through the skin. (11)
Dermal cells include fibroblasts, which secrete extracellular fibres, nerve fibres and immune cells. The abundant immune cells plus lymphatic vessels in the dermis comprise a skin-associated lymphoid tissue (SALT). Mast cells, macrophages, dermal dendritic cells and lymphocytes all contribute to the front line role of the skin in immune defence. (9) There are twice the number of T-lymphocytes permanently resident in the skin than circulating in the blood. In addition, about 10 per cent of memory T-lymphocytes in the circulation have been pre-programmed to migrate directly to the skin in response to cytokines secreted by keratinocytes. These T-lymphocytes are strongly implicated in the development and progression of psoriasis. (9)
BOX 1. WHAT SUN DOES TO THE SKIN EXPOSURE TO the sun's ultraviolet light damages the skin, which reacts protectively by producing melanin--the process of tanning. Worse damage is done when extended exposure leads to sunburn. However, exposure to the sun is necessary for the body to make vitamin D, the lack of which causes a variety of diseases. Melanin units in the skin are made up of melanocytes and keratinocytes. Exposure to ultraviolet radiation (UV light) causes DNA damage in the nuclei of keratinocytes, which then produce a hormone that stimulates neighbouring melanocytes to synthesise melanin. Melanin is packaged into vesicles called melanosomes and exported to the damaged keratinocytes where it concentrates over the top of the nucleus to prevent further UV damage--this is the process of tanning. (20) Mutations or polymorphisms in the genes that regulate melanin production or DNA repair increase risk of skin cancers, including melanomas, and cause poor tanning. Sunburn (solar erythema) occurs where UV damage is sufficient to injure or kill keratinocytes, thus triggering an inflammatory process--local vasodilation and infiltration by mast cells, lymphocytes and neutrophils. Damage also occurs to Langerhans cells, which may contribute to (non-melanoma) cancer development through loss of immune function. (21) However, exposing the skin to the sun is necessary for the body to synthesise vitamin D. UV-B light (which is entirely blocked by glass) triggers synthesis of the vitamin D precursor from cholesterol molecules in the granular and spiny layers of the epidermis. The weaker the sunshine (ie the greater the latitude from the equator) and the darker the skin (melanin absorbs UV-B), the longer the skin exposure required for adequate vitamin D synthesis. Sunscreens also block UV-B sufficiently to impair synthesis. (22) Lack of vitamin D is a known cause of rickets and osteomalacia. Taking vitamin D supplements is known to improve osteoporosis and psoriasis. Deficiency is implicated in a variety of diseases, including obesity and type 2 diabetes, cancer, cardiovascular disease and impaired immune responses. (22)
INFLAMMATORY SKIN DISORDERS
Skin diseases can be caused by barrier dysfunction, immune dysfunction or a combination of the two, which reinforces the effect of each (see Figure 1). Chemical or mechanical breaches of the skin barrier (such as with contact dermatitis) can go on to activate abnormal immune responses, such as the development of allergic contact dermatitis. Ichthyoses, a group of genetic skin disorders, are associated with defects in the gene for filaggrin that affect barrier function of the epidermis and thus cause build-up of stratum corneum (hyperkeratosis) and scaling.
Atopic dermatitis (AD)
Numerous genetic polymorphisms have been linked to the development of AD, including those which control signalling and immune cell activity. However, the strongest evidence lies with the filament aggregating protein filaggrin. (4) Filaggrin is essential to the differentiation of the stratum corneum and to forming the skin barrier regulating not only the exit of water, but also the entry of allergens, chemical irritants and pathogens. Filaggrin is responsible for hydrating the stratum corneum, and its breakdown products contribute to maintaining an acidic pH on the skin's surface. (12)
Defects in the barrier due to abnormal filaggrin allow deeper penetration of allergens and irritants, and drive the skin's immune system toward an allergic pathway, rather than pathogen-response pathway. Patients with AD are colonised or infected by pathogenic organisms, especially S. aureus (including Methicillin-resistant S. aureus MRSA), where innate and adaptive immune responses are sufficiently abnormal, and the antibacterial function of the stratum corneum sufficiently compromised. These pathogens are capable of secreting super-antigens that trigger pruritis and inflammation, which is resistant to treatment with antihistamines. (4) Figure 2 (see p22) illustrates the possible sequence of events in the development of AD.
Two main genetic defects are associated with psoriasis, both affecting immune function, causing abnormal inflammation. The systemic diseases that accompany psoriasis (cardiovascular disease, cancer, psoriatic arthritis etc) may also be associated with inflammatory dysfunction. (13)
Activity in the epidermis is significantly affected in a person with psoriasis. Movement of keratinocytes up through the layers of the epidermis is accelerated--occurring 10 times faster than normal. This causes: (9)
* Thickening of the epidermis.
* Loss of the granular layer of keratinocytes.
* Hyperkeratosis (thickened stratum corneum).
* Parakeratosis (retention of nuclei in stratum corneum).
* Abnormal keratin deposits.
The pathway to psoriasis involves both keratinocytes and immune cells. Susceptible keratinocytes can be triggered by injury, infection or medications. The release of AMPs in response to these triggers activates dendritic cells, and then, through a chain of cytokine signals (including interferons, interleukins and tumour necrosis factor), local T-lymphocytes. An inflammatory response follows. The lymphocytes release more cytokines that further activate keratinocytes and the inflammatory response becomes amplified. As the disease be comes chronic, psoriasis lesions develop in the dermis, which consist of dendritic cells, T-lymphocytes and macrophages all secreting cytokines that perpetuate the inflammatory response. (9) These cytokines, especially interleukin-17 and tumour necrosis factor, are also powerful stimulators of keratinocyte proliferation and thus produce the effects seen in the epidermal layer of patients with psoriasis.
MANAGING INFLAMMATORY SKIN DISORDERS
Managing skin disorders involves both topical and systemic therapies (depending on severity) to relieve symptoms, and increasingly includes the use of disease-modulating drugs.
Moisturisers can be used to manage dry skin (xerosis), reduce TEWL, and soften and hydrate surface epidermal layers. The efficacy of specific moisturisers in meeting these aims depends on the composition: (14)
1. To soften and lubricate--emollients such as soy sterols, glycol or glycerol stearate are needed.
2. To reduce water loss--occlusive agents such as dimethacone, petrolatum or mineral oil are needed.
3. To rehydrate--humectants such as glycerol, lactic acid and urea should be ingredients in the moisturiser.
Moisturisers are an essential component of AD therapy--alleviating symptoms, reducing flare-ups, and lessening the dose of topical anti-inflammatories/steroids. Emollients are recommended for managing psoriasis, to help lift scale and reduce fissure development. (15)
Steroid therapy ranges in potency from mild to very strong, depending not only on dose but also on how they are delivered and how deeply they penetrate the skin. (16) Topical steroids are effective for managing both AD and psoriasis, although there is a lack of long-term studies on associated tachyphylaxis (reduced reaction to a drug) and systemic adverse effects. (14,16) There is also considerable uncertainty about dosage, and frequency and duration of application. (15,16)
Calcineurin inhibitors (tacrolimus, pimecrolimus) are second-line topical anti-inflammatories that block T-lymphocyte activation and production of pro-inflammatory cytokines. They are useful as an alternative to steroid creams in sensitive skin areas such as the face, where steroids are not working or if steroid therapy has been prolonged. (14)
Topical antimicrobials and antiseptics are not recommended for use in AD. There is little evidence these provide any improvement and there are concerns about promoting bacterial resistance. Bleach baths may be of some use in moderate to severe AD. (14)
Coal tar has been used for nearly 100 years to manage psoriasis. Little is known about the active ingredients of coal tar or how it works in psoriasis, but it does reduce pruritis and infection, and helps to normalise keratinocyte function, reducing plaque formation. Unfortunately, it is very smelly and stains both skin and clothing. (15) Coal tar has been linked to cancers in miners and other workers, but studies have shown no increased risk for people using it to treat psoriasis. Coal tar is frequently used in combination with phototherapy (Goeckerman regime). Other antiplaque topical medications include salicylic acid, dithranol and calcipotrol.
Phototherapy with UV-B light has been used, with increasing refinement, for many years to manage psoriasis and AD. UV light is immunosuppressive, inhibiting the action of Langerhans cells and T-lymphocytes. It also reduces keratinocyte proliferation in psoriasis. Patients must be carefully monitored for skin cancer, during and after treatment. (17,18)
Systemic immune modulating agents
Systemic immune modulating agents are drugs that affect immune system function, but are not directly targeted at the causative pathways of psoriasis or AD. Systemic therapy is more common in psoriasis, and used in AD only where topical therapy has not worked. Systemic steroids are not recommended in AD due to the risk of adverse effects, except for very short-term use for severe, acute exacerbations. (18)
Methotrexate, ciclosporin and acitretin are commonly used medications for managing psoriasis. All have significant adverse effects that may limit their use in some patients. Methotrexate and ciclosporin are also used to manage severe AD.
Methotrexate inhibits DNA synthesis and acts on both T-lymphocytes and keratinocytes. It is considered the gold standard in psoriasis therapy. (18) Ciclosporin prevents activation of T-lymphocytes and may also affect keratinocytes, while acitretin is a retinoic acid that suppresses keratinocyte proliferation.
Biological targeted therapies
Recent advances in targeting specific molecules involved in inflammatory skin disorders have shown great promise. Targeted therapies should, theoretically, have fewer side effects than systemic immune modulating agents. Many are antibodies designed to work against specific signalling molecules; eg dupimulab, currently undergoing clinical trials, inhibits interleukin 4 and reduces AD symptoms rapidly. (19)
Adalimumab, etanercept and infliximab are already used in clinical practice, but are very expensive. All these target tumour necrosis factor-alpha to manage psoriasis. There is not sufficient data about their usefulness in AD to recommend therapy. (18)
These newer, targeted therapies have so far demonstrated much greater efficacy in managing skin disease, with generally fewer adverse effects, than older types of medication. However, they suffer from a lack of long-term safety data and this, added to their high cost, limits current use. Each newly developed targeted therapy increases our understanding of the mechanisms underlying these diseases, and, in turn, opens up new possibilities for management^ In the near future, we should see increasingly refined targeting of individual molecules in these disease pathways that, individually or combined, might revolutionise life for people with inflammatory skin disorders.
* References for this article can be found at www.cpd4nurses.co.nz.
Clarification re adverse effects of inactivated viral vaccines
IN THE CPD article "Vaccines--how and why they work" (Kai Tiaki Nursing New Zealand, Feb 2016, p20-24), it was stated that inactivated vaccines (eg the seasonal influenza vaccine) may occasionally contain live viral particles carrying a risk of infection. Inactivated vaccines do not contain active viral particles. Modern vaccine manufacturing is tightly controlled to ensure precise inactivation techniques, based on knowledge of the complex inactivation kinetics for each virus strain, that balance inactivation against loss of vaccine effectiveness. Strictly regulated quality control methods require that every batch of inactivated vaccines be screened for live viruses through prolonged incubation. Effectively there is no risk of live virus transmission through inactivated vaccines.
Sanders, B., et al. (2014). Inactivated viral vaccines. In Nunnally, B., et al (eds), Vaccine analysis: Strategies, principles, and controls. Springer.
After reading this article and completing the accompanying online learning activity, you should be able to:
* Discuss recent advances in the understanding of skin structure and function.
* Outline the roles of genetics, immunity and skin structure in the development of inflammatory skin disorders.
* Describe current and developing therapeutic regimens to manage and control inflammatory skin disorders.
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Go to www.cpd4nurses.co.nz to complete the learning activities for this article. The online service costs $19.95 per article.
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Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
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|Title Annotation:||CPD + nurses; treatment of skin diseases by nurses|
|Publication:||Kai Tiaki: Nursing New Zealand|
|Date:||Apr 1, 2016|
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