Skin diseases Flashcards
1
Q
What are the functions of the skin?
A
- Protective barrier- physical and chemical
- Involved in mechanical support
- Prevents loss of moisture
- Reduced harmful effects of UV radiation
- Sensory organ- touch, temperature, pressure etc
- Helps regulate body temperature
- Immune organ to detect infections
- Involved in production of vitamin D
- Excretion of waste products
2
Q
How many distinct layers does the skin have?
A
3 distinct layers:
- Epidermis - On the outside, consists of layers of epithelial cells and these replace themselves every 2-3 days, it doesn’t have a blood supply - The oxygen and nutrients required for this area actually comes from the capillaries in the lower dermal layer
- Dermis - Middle layer, vascular rich areas, hair follicles, different types of glands, connective tissue rich area
- Hypodermis - Full of adipose tissue
3
Q
How many distinct layers does the epidermis have?
A
5 distinct layers:
- Stratum basal
- Stratum spinosum
- Stratum granulosum
- Stratum lucidum
- Stratum corneum
4
Q
What are the cell types available in the epidermis?
A
Keratinocytes:
- Main cell type
- Derived from stem cells
- Starts of in the basal areas and as they progress up they become flatter and eventually dead and are shed off
Merkel cells:
- Present in the stratum basal
- Can detect light or discriminatory touch
- Attached to sensory neurone and are found in different locations in the skin
Melanocytes:
- Near the basal region, in the stratum spinosum
- These produce melanin, which protects against UV
- Found throughout the skin
Langerhans cells (APC):
- They are dendritic cells, very important in detecting self and non-self
- They sample the populations of bacteria that live in the surface of the skin and let us know if they are safe
T cells:
- CD8 positive cells, which are ready to attack just incase we have foreign invaders, therefore the dendritic cells can present antigens to the CD8 T cells.
5
Q
Is the epidermal layer thick or thin?
A
Thin layer
6
Q
What is the stratum corneum layer enriched with?
A
Lipids and keratin
7
Q
What happens to the skin cells as they age?
A
They flatten, start to lose their nuclei and eventually die.
8
Q
What does keratinocytes secrete?
A
Interleukin-1 beta, which is important in maintaining homeostasis but also in inflammation where the cells can become damaged.
9
Q
What does melanocytes produce?
A
Produce melanin in the skin
10
Q
What is melanin produced from?
A
Tyrosine
- Tyrosine is metabolised into Dopa and the Dopaquinone by Tyrosinase.
11
Q
In the presence of Cysteine, what does Dopaquinone become metabolised into?
A
Pheomelanins, red pigments e.g. people with red hair, freckles etc
12
Q
How does Dopaquinone become metabolised into Eumelanins?
A
Dopaquinone becomes metabolised into Leucodopachrome and then Dopachrome.
Eumelanins are the black and brown melanin that are present in darker skin
13
Q
How many distinct layers does the Dermis have?
A
2 distinct layers:
- Papillary layer (next to the epidermic layer)
- Reticular layer
14
Q
What is the papillary layer of the dermis?
A
- Its about 20% of the dermis
- It’s a very vascular rich region (contains lots of capillaries which release oxygen and nutrients near the epidermis, therefore the bottom layer of the epidermis have sufficient oxygen and nutrients and retain their nuclei. But as you go further away from the oxygen and nutrients, and the capillaries of the dermis, the cells become more flattened in the skin.)
- Lots of connective tissue - particularly collagen
- Papillae’s that stick out which increase the surface area, therefore more exchange of oxygen and nutrients into the epidermis.
15
Q
What is the Reticular layer of the dermis?
A
- Takes up majority of the dermis
- Consists of dense irregular connective tissue
- Also consists of elastin and fibrillin. So elastin makes it more elastic and collagen makes it strong
- Consists of several types of immune cells
16
Q
What are the Meissner’s Corpuscles?
A
Receptors for light or discriminative touch and up near the epidermal layer.
17
Q
What are the Pacinian Corpuscles?
A
These can detect vibration in the skin
18
Q
What does the root hair plexus do?
A
Detects fine touch that is detected from the hair shaft, so any movements of the hair shaft. Therefore sensory receptors.
19
Q
What does the Sebaceous (oil) glands do?
A
They produce the oil that keeps the skin moist. Also produces the oil that keeps the hair moist and prevents it from cracking.
The oil floats to the surface and protects the outer keratin layers of the skin as well as the hair.
20
Q
What happens to the sebaceous glands when we get acne in adolescence?
A
The sebaceous glands can cause problems during adolescence when we get acne, where we get clogging of these sebaceous glands
21
Q
Where are apocrine sweat glands present?
A
In the armpit and pubic region.
They produce a protein rich sweat that supports the growth of surface bacteria. They also produce a specific odour.
22
Q
What kind of sweat does Eccrine sweat glands produce?
A
They produce extra watery sweat.
23
Q
How does sweat contribute to regulating body temperature?
A
When sweat is released onto the skin it evaporates. The amount of sweat that is released can depend on the external temperature, the amount of heat generated by skeletal muscle activity and emotional factors (e.g. sweating when nervous).
Hormones can also release sweat, e.g. during menopause there’s an increase in sweat production for instance with night sweats.
24
Q
How does the skin on the face differ from other parts of the body?
A
- In the face we have sebaceous glands connected to the hair shafts and hair follicles.
- There are eccrine sweat glands present
- Environmentally exposed - This is an area that is exposed to the outside all the time
25
How does the skin on the palm of your hand differ from other parts of the body?
- There is a thick layer of skin - Thick stratum corneum for protection
- Lots of eccrine sweat glands present in the region
- Hairless
26
How does the skin in the Axilla (armpit area) differ from other parts of the body?
- There are apocrine sweat glands present, which tend to be in more humid areas
- High density of hair
- Occluded, humid environment
27
What 3 things does the subcutaneous fat layer (hypodermis) act as?
- Mechanical protector (physical protector)
- Thermal insulator (fat is a good insulator)
- Energy store
28
What does the thickness of the subcutaneous tissue (hypodermis) depend on?
Thickness of the layer depends on the whole body adiposity, therefore how much fat we have in the whole body.
We need a minimal amount to protect our skeleton and organs in our body.
29
What 2 factors are used in heat regulation?
- Subcutaneous fat pad (hypodermis)
- Skin blood supply
30
List the immune cells in our skin.
- Langerhans cell (dendritic cells)
- CD8+ T cells
- Keratinocytes
- Dermal dendritic cells
- Plasmacytoid dendritic cells
- CD4 cells (T Helper 1,2 and 17)
- Natural Killer T cells
- Gamma delta T cells
- Macrophages
- Mast cells
- Fibroblast
31
In what situations is the immune system ready to react in the skin?
- Wound/cut in the skin
- Burn from UV light e.g. sunburn
- Toxins/chemicals or allergic to the skin
- Insect bites
When these happen we mount an immune response and as a result of that we get inflammation.
32
What different factors cause a signal-mediated response in our keratinocytes and immune cells in the epidermis and the dermis which lead to an inflammatory response?
- Infectious agents: Bacteria, Fungi, Viruses, Parasites etc
- Toxins: Chemical, Radioactive, UV, Biological etc
- Physical stresses: Mechanical, Burns, Trauma, etc
33
What is the ultimate goal of inflammatory response in the skin?
It is a protective response; We are trying to remove the initial cause of the injury, whether its infectious agents, toxins or physical stresses and repair the damage. Therefore end up with a lot of dead cells, necrotic cells and tissues that need to be destroyed so that it can return back to normal.
34
What is the purpose of the skin microbiome?
It protects us from disease
35
What is the downside of skin microbiome?
- Exacerbate skin lesions
- Promote disease
- Delay would healing
36
What is the skin microbiome?
Collection of all the microbes that live on the human skin such as bacteria, fungi, viruses and mites.
37
How does microbes directly inhibit pathogen growth?
- They are taking up the space, therefore pathogens don't have space to grow. They also take up the nutrients on the skin, therefore the pathogens can't grow because they have nothing to eat.
- They produce AMPs and bactericidal compounds that can kill pathogenic micro organisms.
- They inhibit S.aureus biofilm formation
38
How do microbes react with the innate immune system locally?
- They help to tune our local cytokine production
- They get presented to the antigen presenting cells which are the dendritic cells/langerhans cells and that helps us to present these antigens to the T cells to be recognised as self.
39
How to microbes enhance host innate immunity?
- Increase AMP (anti microbial production) production
- Help to decrease inflammation after injury
- Strengthen epidermal barrier
40
What happens (step by step) if a change occurs in the microbe community?
1. A change could be an infection, taking long term antibiotics, or overgrowth, can all change the microbial community living on the skin.
2. This can then lead to an inflammatory response on the skin, which then produced proinflammatory cytokines causing inflammation.
3. This inflammation can damage the barrier to the skin, which can then allow both the immune system to infiltrate into the area and also get a disrupted physical barrier.
4. This then allows microbes to enter areas which they normally would not enter, and penetrate sterile tissues which can cause major problems.
41
What changes can we have on the skin that can affect the microbes?
- Chronic condition i.e. diabetes - which can cause wounds to occur
- Injury
- Genetic predisposition
This changes the microbial community that's on the skin, because it can be taken over by potential pathogens and these pathogens can enter areas they shouldn't and cause an inflammatory response.
This inflammation can then break down the barrier or impair would healing and cause more problems.
42
What is a wound?
It is a break in the epithelial integrity of the skin. It affects the epidermis but it can affect the dermal layers and even deeper layers, through the hypodermis and muscles and into the bone.
43
What is a superficial wound?
- Tends to be associated with the epidermal layer
- Damage to the epithelium (outer layer)
- Heals rapidly through regeneration of epithelial cells
- No bleeding as there's no vascular system in the epidermis
44
What is a partial thickness wound?
- Involves the dermal layer
- There is bleeding due to vascular damage as its a very rich area for blood vessels
45
What is a full thickness wound?
- Involves the subcutaneous fat and deeper (even muscle and bone)
- Longest time to heal - new connective tissues required
- Contraction during healing - will take a while for that scar
46
What are the 4 main stages of wound healing?
1. Bleeding : Where bleeding occurs. You get injury to the skin, therefore leading to bleeding and this is called haemostasis because we want to form a blood clot and stop the bleeding.
2. Inflammation : In this case we want to stop any infections from occurring, we have lots of immune cells coming into the area, and provide a framework for new blood vessel growth as well.
3. Proliferation : In this stage were making more connective tissue, to try and replace the damaged tissue and pull the wounds closed and form a new epidermal layer which is very delicate.
4. Remodelling phase : Where we try to bring it back to much to normal as possible, decrease the amount of immune cells in the area and contract the area to what it used to look like and you end up with this avascular scar on the surface.
47
How long does it take for wound healing to occur?
1. Bleeding stage takes less than a day
2. The inflammatory stage takes up to anything between 1 - 10 days. But after 1 day is when the neutrophils come in and start to cause inflammation, so it's peaking after about 1 day. Around about 2-3 days you get granulocytes, macrophages, cytokines etc coming in. You get phagocytosis happening for these few days which is getting rid of the bacteria or any infection that might be around, but also eating up the damaged tissue and getting ridding of the dead tissues so that it can be replaced.
3. Proliferation stage: After about 3 days we begin to see proliferation phase and this is where we being to deposit the matrix down. We're making collagens, fibronectin and proteoglycans which are involved in connective tissue. Also fibroplasia occurring (fibroblasts are proliferating), angiogenesis occurs (new blood vessel formation), re-epithelialization (new delicate cover over the wound) and extracellular matrix synthesis.
4. After about 10 days up to 2 weeks to a month, after the wound has occurred, proliferation has ended and onto the remodelling phase. We get a strengthening of this area, increase in tensile strength, decrease of cells in the area and decrease of vascularity in the area. Remodelling the connective tissue and extracellular matrix. This can take up to almost 1 year, for it to get back to normal, depending on how deep the wound is.
48
What cells and mediators are involved in the inflammation process of acute wound healing?
Neutrophils and macrophages (very important in this stage as they will produce MMPs, ROS, hydrogen peroxide, range of cytokines such as IL and TNF, and growth factors such as VEGF, TGFB, FGF, PDGF)
49
What cells and mediators are involved in the granulation and neoangiogenesis processes of acute wound healing?
Fibroblasts, macrophages, endothelial cells, MMPs, prolyl hydroxylase, IL, TNF, TGFB, VEGF, PDGF, KGF
50
What cells and mediators are involved in the re-epithelialization process of acute wound healing?
Keratinocytes, MMPs, EGF, KGF
51
What cells and mediators are involved in the tissue remodelling process of acute wound healing?
Fibroblasts, collagen fibre cross-linking, MMPs, TGFB
52
What happens during haemostasis?
1. First thing that happens after injury is that blood seeps into the wound.
2. Injured vessels contract - to limit the amount of blood that leaks through into the surrounding tissues.
3. Coagulation cascade activated by tissue factor very quickly to try and form a clot and limit the leakage and bleeding in the area.
4. Clot formation and platelet aggregation
5. Platelets trapped in clot release PDGF, IGF, EGF, TGF-B which attract and activate fibroblasts, macrophages and endothelial cells.
6. Also release serotonin, which increases vascular permeability - serotonin allows the blood vessels to relax again and increase vascular permeability because you want the immune cells (e.g. neutrophils and monocytes) to come into the area, therefore we need to increase the size of our blood vessels to allow more immune cells to come in.
53
What happens during early inflammatory phase?
1. Activation of complement
2. Infiltration of neutrophils within 24-48h
3. Diapedesis into wound and phagocytosis of bacteria and foreign particles, with ROS and degrading enzymes - prevent infection and eating up dead tissue
4. Dying cells cleared by macrophages or extrusion to wound surface
54
What happens during late inflammatory phase?
1. Blood monocytes arrive and become macrophages (48-72hr)
- Key cell type for repair
- Cytokines and growth factors to recruit fibroblasts, keratinocytes and endothelial cells to repair damage
- Collagenases to degrade tissue
- Poor wound healing when inadequate monocytes/macrophages
2. Lymphocytes enter wound (>72 hr) and are involved in remodelling
55
What happens during the proliferative phase (72h-2wks period)?
1. Fibroblast migration
- Produce fibronectin, hyaluronan, collagen, proteoglycans
- Proliferate and construct new ECM
2. Collagen synthesis
- Strength and integrity
3. Angiogenesis
- TGF beta and PDGF from platelets, TNF and bFGF from macrophages
- Capillary sprouts invade fibrin/fibronectin-rich wound clot and organise microvascular network
4. Granulation tissue formation
- Mainly proliferating fibroblasts, capillaries, macrophages in matrix of collagen GAGs and fibronectin and tenascin
5. Epithelialisation
- Single layer of epidermal cells migrate from wound edges to form delicate covering, basal cells increase proliferation, new basement membrane.
- EGF stimulates epithelial mitogenesis and chemotaxis, bFGF and KGF stimulate proliferation
56
What happens during the remodelling phase (long time period)?
1. Matrix matures and remodels
- Fibronectin and HA broken down
- Collagen bundles increase in diameter and strength (80% of strength of original)
- Ongoing collagen synthesis and breakdown by TGF-beta and MMPs
- Collagen becomes more organised and shrink to bring wound margins closer together
- Fibroblasts and macrophages apoptose
- Capillary outgrowth halted and blood flow reduced
- Acellular (no cells around), avascular (no blood vessels) scar results
57
What happens when the wound does not go back to normal?
You get a chronic wound and impaired wound healing. This usually happens at the inflammatory stage or proliferative stage.
This is due to disturbances in growth factors, cytokines, proteases, cells
58
What local factors affect wound healing (e.g. post surgical)
- Pressure
-Mechanical injury/trauma
- Infection/foreign substances
- Oedema
- Necrosis
- Topical agents
- Lack of oxygen or nutrients delivery (Ischemia)
- Desiccation and dehydration
59
What systemic factors affect wound healing (e.g. post surgical)
- Old age (cells don't work as well, collagen is not as strong, elastin is not elasticated enough etc.)
- Obesity
- Chronic diseases e.g. diabetes (most common cause), anemia
- Connective tissue disorders
- Immunosuppression
- Smoking
- Malnuttrition
- Vascular insufficiency
- Stress
- Radiation or chemotherapy
60
What are the different causes of chronic wounds?
1. Neuropathy - Diabetes mellitus, spinal injuries
2. Ischemia (lack of oxygen and nutrients in the area) - Atherosclerosis, PVD, Microangiopathy (DM)
3. Peripheral oedema - DVT, varicose veins, renal or cardiac failure
4. Pressure - Poor mobility, spinal cord injuries, dementia, diabetes mellitus, old age, terminal illness
5. Others - Connective tissue disorders leading to vasculitis, systemic diseases, malignancy, smoking, drugs such as corticosteroids and hydroxyurea
61
What do chronic wounds look like?
- There lots of dead tissue in the area which is hard to get rid of - presence of necrotic and unhealthy tissue
- Excess exudate (the wound is weak) and slough
- Lack of adequate blood supply
- No healthy granulation tissue
- Failure of re-epithelialisation (the wound doesn't heal over, so you don't get that cover on the wound so it keeps breaking again)
- Cyclic or persistent pain
- Recurrent wound breakdown
- Clinical or sub-clinical infection
62
What are the 3 types of neuropathy?
- Motor neuropathy
- Sensory neuropathy
- Autonomic neuropathy
63
What happens in motor neuropathy that leads to diabetic ulcers?
- You get damage to the neurons and they're not sending the proper messages.
- This then leads to muscle atrophy and/or bone changes which then leads to a change in gait which causes a deformed foot which ultimately leads to ulcers.
- The change in gait also causes new pressure distribution which causes ulcers
64
What happens in sensory neuropathy that leads to diabetic ulcers?
- In sensory neuropathy you can't detect pain, and if you get an injury and you don't detect the pain then that can lead to a wound which can ultimately lead to an ulcer.
- Ulcers can become infected which can lead to gangrene.
65
What happens in autonomic neuropathy that leads to diabetic ulcers?
- In autonomic neuropathy you get a decrease in sweating so you get dry skin and cracks in the skin which can cause inflammation and injury causing chronic ulcers.
66
What is another word for eczema?
Dermatitis
67
What is eczema?
Inflammation of the epidermis. It is a group of skin conditions that cause dry, irritated, inflamed skin.
68
What is dermatitis?
Inflammation of the dermis
69
What does the inflammatory reaction you see with eczema consist of?
- Erythema (redness)
- Oedema (swelling)
- Oozing
- Papules/blisters
- Crusting
- Thickening
- Scaling/flaking
- Itching
- Burning sensation
70
What are the different types of eczema?
- Atopic dermatitis
- Contact dermatitis
- Seborrhoeic dermatitis
- Dyshidrotic dermatitis
- Nummular dermatitis
- Neurodermatitis
- Stasis dermatitis
71
What is atopic dermatitis?
- Most common type of eczema. It's a chronic disorder where you get periods of flare ups and periods of remissions. And you may get cleared up for long periods before it comes back.
- Often it will disappear during childhood but can return maybe during adolescence or maybe present for the first time in adulthood.
- It is a Type 4 hypersensitivity reaction, so you get an allergic response. It often occurs with other allergies such as asthma or hay fever.
- Eczema + Asthma + Hay fever= Atopic triad
- Atopic dermatitis commonly affects the knees, elbows, wrists, neck and face. Usually in infants it appears on the cheeks of their face.
72
What is usually seen first in the atopic triad?
Eczema
73
What causes atopic eczema?
- Genetic predisposition - presence of eczema in atopic families
- Defect in the filaggrin gene - This filaggrin gene is important for maintaining the skin barrier
- Defects in the skin barrier - where its difficult to repair and difficult to maintain the skin
- This is partially due to lack of anti-microbial peptides that are present
- Over time you get an inflammatory and allergic response in the skin.
- Barrier defects makes the skin in affected patients much more susceptible to infection and to irritation and allows allergy-inducing substances to enter the skin, causing itch and inflammation.
74
Atopic eczema - pathophysiology
1. Allergen in the skin gets taken up by dendritic cells. The dendritic cells are the langerhans cells in the epidermis and present in the dermis as well.
2. The dendritic cells with present the antigen to the T cells causing an expansion of TH2 type cells.
3. These secrete IL-4, and IL-4 activates our B cells to change class of antibodies (class switching) and they produce IgE antibodies.
4. IgE travels in the blood to the mast cells and it gets taken up by the high affinity receptors on the surface of the mast cells, which allows allergens to be taken up. When this gets taken up you get a release of pro-inflammatory mediators which cause the inflammation.
75
Where is eczema usually present on children?
Flexural (cheeks, knees, elbows etc) eczema in children
76
Where is eczema usually present on adults?
Hand eczema in adults
77
What are the clinical features of atopic eczema?
- Dry skin
- Itching (may be severe, especially at night)
- Red to brownish grey patches on affected areas become lichenified.
- Raw, sensitive, swollen skin from scratching
- Skin infections and sores can occur when scratching breaks the skin
78
How can atopic eczema flare ups be prevented?
- Moisturisers
- Identify and avoid triggers if possible
- Mild soaps and short showers/baths
78
What can cause flare ups of atopic eczema?
- Heat
- Dust
- Irritants
- Smoke
- Stress
- Certain foods (particularly in children)
- Soaps
- Feeling unwell or having an infection
79
How do you treat atopic eczema?
- Emollients (to keep the moistures in the skin)
- Topical corticosteroids (will work locally to inhibit the inflammation that's going on)
- Antibiotics (if any infections present)
- Phototherapy
IF THIS ISN'T ENOUGH THEN NEXT STEPS ARE:
- Systemic corticosteroids (come with side effects)
- Topical calcineurin inhibitors (TCLs) - Pimecrolimus and tacrolimus (these work by inhibiting the T cell response, so preventing the T helper cells from secreting IL-4)
IF THIS ISN'T ENOUGH THEN NEXT STEPS ARE:
- Immunosuppressants - Ciclosporine, azathioprine (work by inhibiting T cell responses)
- Dupilimumab - mAb inhibiting IL4/IL13 signalling (targeted therapy - prevents the class switching on B cells)
- Alitretinoin - for chronic hand eczema refractory to steroids (retinoid) (It is a form of vitamin A and given when you don't get responses from steroids)
80
What causes contact dermatitis?
Many substances either in the home or the workplace are responsible.
There some kind of stripping of the natural oils in the skin.
Quite often seen in the hands, arms, face or legs - exposed areas of the body.
81
What are the 2 types of contact dermatitis?
1. Irritant contact dermatitis
2. Allergic contact dermatitis
82
Contact dermatitis is common in wet work environments. Give a few examples.
- Healthcare
- Hairdressers
- Catering
- Labs
- Cleaners
- Industrial factory workers etc...
83
Atopic eczema patients have increased susceptibility for contact dermatitis as well. True or False
True
84
Name some examples of irritants that are involved in irritant contact dermatitis.
- Toxic substances e.g. an acid
- Long term use of water/soaps/detergents/solvents
- Dilute acids or alkali
- Excess handwashing
- Dribble rashes
- Nappy rashes
- Can occur under jewllery e.g. rings
85
How can irritant and allergic contact dermatitis be distinguished from each other?
- By using a patch test as they can be used to pick up allergens
86
What 2 factors are important in determining how serious the irritant contact dermatitis?
- Amount of exposure
- How long your exposed
87
What is allergic contact dermatitis?
- Majority of this is related to workplace - occupational skin disorders
- Type 4 hypersensitivity reaction
- Over the time of exposure, there's a build up immune response to the allergic reaction
- Caused by things like nickel, rubber, perfumes, preservatives in cosmetics, dyes, latex in gloves etc
- Diagnosis by patch testing
88
Irritant contact dermatitis - Pathophysiology
It is an innate immune response. The irritant/toxin directly affects the keratinocytes and these will switch on and secrete lots of pro-inflammatory cytokines and the dendritic cells. These will then cause local responses in the keratinocytes but also cause the endothelial cells to be up regulated, which will allow vasodilation to occur, which will allow cellular recruitment into the skin area e.g. neutrophils, macrophages, lymphocytes and mast cells. These will then cause the local inflammatory response.
89
Allergic contact dermatitis - Pathophysiology
It is a combination of adaptive and innate immunity. You get adaptive immune response that's activating causing the T cells to be activated to produce T reg cells, mast cells and all other pro-inflammatory mediators. You also get activation of the innate immune response, by the keratinocytes which are causing vasodilation and cellular recruitment.
90
How do you treat contact dermatitis?
- Avoid the irritants and allergens that are causing it
- Use emollients to prevent moisture loss and cracking of the skin
- Topical corticosteroids
- Oral corticosteroids
- Alitretinoin (vitamin A) for chronic hand contact dermatitis refractory to steroids (retinoid)
91
What is Seborrhoeic dermatitis (adults)?
It is a common harmless rash with skin flakes, itchy and sore inflamed red skin with greasy looking white or yellow scale.
- Can range from a mild form (dandruff) to severe on the scalp
- Sebaceous skin zones - face, scalp, chest, ears, skin folds, axillae (armpits) and groin but most common on the scalp.
92
What causes Seborrhoeic dermatitis?
Yeast
- Due to overgrowth of Malassezia yeasts, which are part of the normal skin flora but trigger inflammatory response.
- It is not contagious
- It is made worse by stress
- Can vary from day to day, and harder to treat in immunosuppressed patients
93
What is Seborrhoeic dermatitis (infantile)?
- Sometimes called cradle cap
- Infants aged 3-8 months
- Yellow, waxy scales on the scalp, thick and difficult to remove (often removed by combing or using an oil to help flake them off)
- Pink flaky patches on forehead, eyebrows, behind ears and nappy areas
- It is due to developing sebum glands and caused by Malessezia yeast
94
How does the Malessezia yeast cause inflammation?
They metabolise into fatty acids which penetrates the skin and causes inflammation.
95
How to treat Seborrheic Dermatitis in Infants?
- Emollients or mineral oils (for the scalp)
- Topical steroids with anti fungal (for the body)
96
How to treat Seborrheic dermatitis in adults?
- Anti-yeast shampoos, with ketoconazole, Zn pyrithione, Se sulphide
- Steroid scalp lotions/mousses
- Topical mild corticosteroids with salicylic acid (for scalp)
- Topical mild corticosteroids with anti-yeast - creams/ointments (clotrimazole, miconazole and nystatin)
- Oral antifungals (severe cases)
97
What other forms of dermatitis are there?
- Nummular (discoid) dermatitis
- Neurodermatitis
- Stasis dermatitis
- Dishydrotic dermatitis
98
What is phototherapy?
Phototherapy uses lightwaves to treat certain skin conditions.
99
What is psoriasis?
- It an autoimmune disease. It's a chronic inflammatory disease with periods of flare ups and remissions.
100
What happens during psoriasis?
Normal skin cells (keratinocytes) are produced much faster than they are shed. This results in an itchy skin lesions/plaques - they're pink/red underneath with white scales on top. They are in variety of shapes and sizes - can split and cause infections - can be painful
- Can develop psoriatic arthritis which affects the joints and tendons
- It is not a contagious disorder
101
What are the types of psoriasis?
- Plaque psoriasis
- Scalp psoriasis
- Guattate psoriasis
- Nail psoriasis
- Psoriatic arthritis
- Psoriasis in sensitive areas - armpits, genitals and skinfolds
102
What is plaque psoriasis?
- Mose common type of psoriasis
- Red, itchy, sore plaques with white or silvery scales - well demarcated (distinguished- you can see where the plaque starts and stops)
- The reason why its red underneath the flakiness or scales is because there's increased blood flow to the area to try and cope with the speed at which the skin cells are replicated
- Can occur anywhere on the body - usually different type if on plans or soles or where skin touches skin
103
What is scalp psoriasis?
- Thick build up of scaly skin leading to dandruff-like flakes
- Visible around the hairline, forehead, neck and ears
- If its severe it can cause hairless or thinning of the hair
104
What is guttate (tear drop or rain drop) psoriasis?
- Bright pink or red on fair skin, less red and more darkening on dark skin
- Widespread across torso, back and limbs
- Usually eventually clears up
- Common in children and younger adults
- Often triggered by strep throat
105
What is pustular psoriasis?
- Small white or yellow fluid-filled blisters (pustules) on top of red or darkened skin - turn crusty when burst
- Appears on palms of hands or soles of feet
- Can become generalised all over the body, and if this happens it needs urgent attention
- Can be painful and requires dermatologist for treatment
106
What is nail psoriasis?
- Can affect only the nails
- Fingernails and/or toenails
- Mild to sever and often mistaken for fungal infection
- Nail discolouration, pitting, crumbling, cracking, splitting, detaching of the nails
107
What causes psoriasis? (aetiology)
- It is an autoimmune disease and has a genetic predisposition, so around 1 in 4 children of affected parents will get psoriasis. There are several other genes that can be involved as well - several susceptibility loci.
- Keratinocytes normally take up to 3-4 weeks to work up from basal layer to shedding, however in psoriasis this takes around 3-44 DAYS, therefore the skin doesn't have time to get rid of/shed those cells so therefore you get a buildup of keratinocytes in the area.
- Inflammatory cells increased in all layers
- Trigger is often an outside event: E.g. throat infection (streptococcal), flu, stress or injury to skin, virus (HIV or HPV) or withdrawal or corticosteroids.
- Sometimes the disease is precipitated by NSAIDs, lithium or the use of beta adrenal receptor antagonists.
108
Explain the pathogenesis of psoriasis.
There is a genetic predisposition, for instance a mutations in the PSORS1 gene, interleukin 23R or interleukin 12B and in combination with environmental factors such as stress, microorganisms, drugs, trauma and smoking. These genetic and environmental factors combine to stress the cells, the keratinocytes become stressed and when stressed they produced pro-inflammatory cytokines which activates the dermal dendritic cells. At the same time the stressed keratinocytes also release their DNA and LL-37. The DNA that is released and the LL-37 combine to form complexes (DNA-LL-37 complexes). Our immune system doesn't recognise these complexes and thinks their foreign, hence their the auto antigens. These complexes then get taken up by the dendritic cells and presented to the T cells. The dendritic cells also secrete IL-23, which is a good target in psoriasis as well as IL-12. This basically switches our T cells, therefore clonal expansion of the T cells and we get T helper 1 cells and T helper 17 cells. The T helper cells then take up the antigens and produce cytokines. The Th1 response produces interferon gamma and TNF alpha, which activates our dendritic cells and also the keratinocytes and causes more inflammation. It causes the keratinocytes to produce chemokine. The chemokine set of a chemokine gradient which allows the T helper cells and macrophages to go into the keratinocyte layer, and we get clonal expansion of T helper cells, more production of pro-inflammatory cytokines, which helps the keratinocytes to grow more (growth factors) and ultimately hyper-proliferation of the keratinocyte layer. Also get activation of fibroblasts, hence more production of collagen and keratinocytes. Overall, the keratinocytes get made too quickly therefore not enough time to shed them off. This then allows more neutrophils and other monocytes to enter the area, hence more inflammation.
109
What are the treatment options used to treat psoriasis?
1. Unique to each individual
2. Topical treatments:
- Moisturisers and emollients (to prevent water loss and cracking)
- Vitamin D derivatives (calcipotriol, tacalcitol, calcitriol)
- Topical steroids (eumovate, betnovate, dermovate)
- Dovobet (betamethasone and Vit D derivative) - Combination
- Coal Tar preps - for the scalp (anti-inflammatory and anti-scaling)
- Dithranol - for well-defined plaques not on sensitive areas (quite toxic)
- Calcineurin inhibitors (inhibits the T cell responses)
3. Phototherapy
4. Systemic treatments:
- Immunosuppressants - methotrexate and ciclosporin
- Vitamin A derivative (Acitretin)
- Apremilast - inhibits phosphodiesterase 4
- Dimethyl fumarate - activates Nrf2
- Anti-TNF (infliximab, adalimumab, etanercept, certolizumab)
- Anti-IL23 (ustekinumab (anti-IL12/IL23), guselkumab, rizankizumab, tildrakizumab)
- Anti-IL17/IL17A (secukinumab, brodalumab, ixekizumab)
110
What is psoriatic arthritis?
- Inflammatory joint disease affecting both joints (e.g. knees, hands and feet) and tendons (e.g. heel and lower back)
- Relapsing and remitting
- Generally occurs after skin lesions however can occur first
- Not linked to severity of psoriasis
- Joints become tender, swollen and stiff- worse in morning and ease with exercise
- Inflammation of tendons without joints
- Often associated with nail psoriasis
111
What are the treatment options available for psoriatic arthritis?
- Painkillers
- NSAIDs (ibuprofen, diclofenac, COX-2 inhibitors)
- Corticosteroids
- DMARDS - leflunomide
- Biologicals (Anti-TNF, Apremilast, Tofacitinib)
*Tofacitinib is a JAK inhibitor, JAK is on the IL6 signalling pathway, hence a kinase that responds to cytokines particularly IL6. So IL6 induces Janus kinases which induces a transcription factor which causes the effects of IL6 in the cells. So we can target JAK as well. *
112
Give some examples of other skin disorders.
- Acne
- Skin cancer
- Infections (Warts, verrucas, impetigo, fungal infections)
- Pigmentation changes (Vitiligo)
113
What is acne?
- It is a very common skin disorder
- Characterised by blackheads and whiteheads and pustules
- Mostly affects the face, the upper part of the chest and the back where most sebaceous follicles
- Severe acne is inflammatory, but acne can also manifest in non-inflammatory forms
- Lesions are caused by excess oil and dead skin cells clogging up follicles- Propionibacterium acnae grow by feeding on the dead skin cells, triggering inflammation and pus
- In adolescence, acne is usually caused by an increase in testosterone, which accrues during puberty
- Acne scars are the result of inflammation within the dermis brought on by acne
- Treatment options: Benzoyl peroxide, antiseptics, antibiotics, hormonal treatments, retinoids (topically and systemically)
114
What are the 3 types of skin cancers?
- Basal cell carcinoma
- Squamous cell carcinoma
- Malignant melanoma
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What is basal cell carcinoma?
- It is a slow-growing and locally invasive tumours
- It is caused by UV exposure and proliferation of basal keratinocytes
- Commonly starts on the head and neck
- Morbidity is related to local tissue invasion and destructions
- Treatment: Imiquimod cream which enhances immunity in the area which kills off cancer cells
116
What is squamous cell carcinoma?
- Malignant invasive proliferation of epidermal keratinocytes
- Caused by UV exposure
- Common in white skin which burns easily
- Also caused by topical carcinogens - arsenic or chronic immunosuppression
- With treatment overall remission rate is 90%
117
What is malignant melanoma?
- It is a malignant proliferation of melanocytes
- Caused by UV exposure
- Survival of melanoma is based of early diagnosis and early start to treatment
- Limited treatment options
- Most aggressive form of skin cancer
118
What are the risk factors of skin cancer?
- UV exposure
- Intense short exposure in childhood
- Fair skin
- Red and blonde hair
- Blue eyes
- Difficulty to tan
- Freckles
- Benign naevi/dysplastic naevi (birth mark or mole on the skin)
119
What are the 5 signs of melanoma?
A - Asymmetry
B - Border is irregular
C - Colour variegation
D - Diameter (>6 mm)
E - Evolving - any change (e.g. size, shape, colour, elevation, bleeding, itching, crusting)
120
What are the treatment options for skin cancer?
1. Surgery
- Simple or wide
- Sentinel node biopsy (Take a biopsy for the nearest lymph node and look for cancerous cells there, which will determine whether the melanoma has left the area or not)
2. Chemotherapy
- Dacarbazine iv infusion (patients become resistant to very quickly) or Temozolomide oral
- Texanes (docetaxel, paclitaxel) and platinum agents
- Targeted therapy (IL2, Interferon alpha 2b, Ipilimumab (anti-CTLA4), Anti-BRAF, Anti-PD1)
121
What do warts look like?
Small, rough growth, typically hands or feet. There exist in several different types and shapes:
- Most common is round, firm, raised, knuckles
- Verrucas- white, soles of feet, flat
- Plane - clusters- yellowish, smooth, young
- Filiform - long, slender, neck and face
- Periungual - nails, change shape, painful
- Mosaic - tile-like clusters, palms and soles
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What are warts and verrucas?
- They are caused by human papilloma virus - which causes excess keratin production on epidermis
- The virus can spread through close skin to skin contact, contaminated objects e.g. towels, shoes, communal changing areas, more likely to spread if skin is wet, soft and in contact with rough surface.
- Clears up after about 2 years
Treatment
- Salicylic acid containing creams, gels and paints
- Cryosurgery
123
What are genital warts?
- It is very common and sexually transmitted
- May take months or even years to develop after HPV infection
Treatment
- Liquids and creams e.g. Imiquimod, a topical cream that stimulates the immune system to fight papilloma virus by encouraging interferon production
- Keratolysis (shaving off that excess keratin)
- Cryosurgery
124
What is impetigo?
It is a common highly contagious skin infection causing sores and blisters - often Streptococcus/Staphylococcus infections
125
What are the 2 types of impetigo?
1. Non-bullous - nose and mouth, sores quickly burst - leave yellow-brown crust
2. Bullous - trunk, fluid-filled blisters that burst after few days - leave yellow crust
126
What are the treatment options for impetigo?
- Topical antibiotics
- Stay away from other people - contagious
- Severe cases -> systemic antibiotics (e.g. Flucloxacillin)
127
What are fungal infections?
- Several types of infections e.g. dermatophytes and yeasts which result in inflammation
- Fungi invade and grow in dead keratin
Dermatophytes causes:
1. Athletes foot (ringworm growing between toes, itchy flaky red skin, contaminated floors)
2. Nail infections - usually toenails - start from edge to base
3. Ringworm - body, scalp, groin
128
What are the treatment options for fungal infections?
- Small areas are treated with topical application of imidazole (2%)
- Severe cases with systemic anti fungal agents (griseofulvin, itraconazole)
- Immunocompromised patients can get fungal infections (Candida and Aspergillus)
129
What are some example/causes of hypopigmentation?
- Vitiligo
- Decreased production of melanin
- Albinism
- Infection, blisters
- Burns
- Phototherapy
130
What are some example/causes of hyperpigmentation?
- Enhanced melanin production
- Pregnancy, Addison's disease
- UV exposure
- Antibiotics and antimalarials
- Hydroquinone
131
What is Vitiligo?
- It is loss of skin colour in patches- discoloured areas usually get bigger with time
- Affects any part of the body, hair and inside the mouth but more often around eyes, nostrils, mouth, navel, knees and elbows
- Melanocytes die or stop functioning leading to loss of melanin
- Affects people of all races and all skin types
- Not contagious or life threatening and not linked to cancer
- There's no cure for vitiligo
132
What are the 3 types of vitiligo?
- Focal
- Segmental
- Generalised
133
what causes Vitiligo?
- Immune system attacking its own melanocytes
- Autoimmune component
134
Name some triggers of Vitiligo?
- Stress
- Skin damage
- Hormonal changes
- Chemical exposure (phenol)
- Liver/renal disease
135
Explain the pathogenesis?
- Autoimmune component
- Body makes autoantibodies to tyrosine hydroxylate in non-segmental vitiligo
- Increase in ROS production also in mitochondria of affected cells
136
What is the advantage of using skin formulations?
The drug can be applied directly to diseased tissue
137
What is the disadvantage of using skin formulations?
Skin is a highly effective barrier, so its supposed to protect us from the exogenous environment and from toxins, this means that unless the barrier has broken down it can prevent entry of medicines
138
What is the site of action for skin formulations?
Often lower layer of epidermis or dermis so has to pass through lipid rich layers of epidermis - leads to special issues with transdermal delivery
139
Examples of topical formulation
- Solutions (Erythromycin)
- Collodion (Salicyclic acid)
- Suspension (Selenium sulfide)
- Emulsion (lotion)
- Semisolids (ointment, pastes, gels and creams)
- Solids (powders, aerosols)
- Spray (lidocaine)
140
What are the 5 target regions in Dermatology?
1. Surface treatment (e.g. protective layer, insect repellent, antimicrobial, anti fungal, sunscreen)
2. Stratum Corneum (e.g. emollient, keratosis)
3. Skin Appendage (Acne, antibiotics, antiperspirant)
4. Viable epidermis-dermic (Anti-inflammatory, anaesthetics, antihistamine, antipruritic)
5. Systemic treatment (Transdermal)
141
How does transdermal drug delivery work?
Delivering drugs across the stratum corneum and into the systemic circulation.
It works by getting through the stratum corneum, needs to penetrate through the outside layers (keratinocytes) then through the whole of the epidermis and into the dermis and then finally into the vascular system in the dermis in order for the systemic circulation to obtain the drug.
142
What is the transdermal therapeutic system?
Designed to release drug at a rate below the maximal rate for controlled systemic therapy - therefore slower/controlled release of the drug.
143
What the advantages of transdermal skin patches?
- Avoids first-pass metabolism of drug in liver
-Consistent site of absorption i.e. no missing gut absorption window
- Can give constant drug input rate
- Can stop dosing by removing patch
144
Describe the pathogenesis of malignant melanoma?
In the epidermis we have melanocytes in the basal layer, and when proliferation occurs they can turn into benign moles/ benign nevus. Sometimes the grow out of control and you get dysplastic nevus, which cause the asymmetric moles. Overtime you get radial growth phase (RGP) and they now become melanoma cells and they stay in the epidermal layer. Then we get vertical growth phase (VGP) and they expand into the dermal layer. Eventually they become metastatic melanoma as they reach the blood vessels that are in the dermal area and then they can move to other areas of the body to form metastasis.
145
What is Breslow Thickness?
The thickness of the melanoma can determine survival.
<1mm: 5-year survival is 95-100%
1-2mm: 5-year survival is 80-96%
2.1-4mm: 5-year survival is 60-75%
>4mm: 5-year survival is 37-50%
146
What is done to topical glucocorticoids to enhance absorption?
Glucocorticoids derivative with fatty acid esters to make them more lipophilic hence enhancing absorption in the skin.
147
What factors do we need to consider to apply drugs directly to the skin for skin disorders?
- Manipulate the barrier function of the skin (improve the barrier function)
- Responding to infections in the skin: use of topical antibiotics and antibacterial or even anti-inflammatory, to bring down inflammation in the skin.
- Protect the skin from UV damage: Sunscreen and emollient preparation to restore pliability to dry horny layer.
148
How can we get drugs through the skin for skin disorders?
- I.e. skin delivery for systemic treatment
- Transdermal patches for treatment of motion sickness
- Transdermal patches for systemic delivery in angina
- Transdermal patches can be used for many other diseases
149
What is topical delivery system?
- It is intended for extended use
- Localised action on one more layers of the skin - only used on the top layers of the skin
- Reach systemic circulation in sub-therapeutic drug concentration (Only small amounts of the drug will reach the systemic circulation because they get through to the dermis where the vascular system is with the arterioles and venules as well as the capillaries and that allows small amounts of the drug that is designed for the skin to get through there.)
Example: Skin softening (emollient)
150
What is transdermal delivery system?
- Intended for external use
- Skin is not the primary target
- Drugs transport through percutaneous route to systemic circulation (This happens through access of the capillaries, arterioles and venules in the dermis)
Examples: Nicotine patch, Hormones
151
How are creams/ointments used as skin formulation?
1. Creams and ointments are tailored to specific drugs
- Some drugs require water in oil emulsion e.g. Ciclosporin is hydrophobic therefore exists in water in oil emulsion
- Oil in water e.g. for NSAIDs as they are hydrophilic
- Appearance and odour is important otherwise patients won't take them.
2. There are agents to protect the skin and promote repair
- Emollients - rehydrate the skin
- Barrier creams - prevent damage from irritants
3. Novel technologies - Nanocarriers etc. - used to enhance the penetration and absorption of the drug
152
Which skin formulations are semi-solids?
- Ointments
- Creams (O/W or W/O)
- Pastes (e.g. dental paste)
153
What are some examples of transdermal skin patches?
1. Transdermal scopolamine (hyoscine) -> Motion sickness
2. Transdermal nitroglycerin (GTN) -> Angina
3. Transdermal estradiol -> HRT and menopause
4. Transdermal contraceptive -> ethinyl estradiol and noregestromin
5. Transdermal nicotine
6. Transdermal testosterone
7. Transdermal fentanyl
154
What is the intercellular microroute?
It gets through the stratum corneum by between the cells
155
What is the trans cellular microroute?
It gets through the stratum corneum by going through the cells. (Lipid based drugs)
156
Why can't all drugs be delivered across the skin? (transdermally)
It is a very complex process, and only micrograms will get through per hour through the system. So the drugs need to be quite potent, the right formulation etc. in order for transdermal delivery to occur.
157
What factors need to be considered for the choice of drug candidates for transdermal delivery?
1. Physiochemical nature of the drug
2. Potency of the drug (Low amounts of drug crossing the skin means that most drugs delivered transdermally are potents i.e. have very low minimum effective concentration)
3. Timescale of drug exposure (Creams, lotions, ointments applied OD,BD/TDS however patches applied OD or every 72 hours)
4. Site and condition of skin (Subcutaneous (SC) thickness varies across body, Broken or inflamed skin more permeable, Hirsute skin may be more permeable)
5. Formulation (1. Ointment, cream, lotion, gel - Aim is to maximise drug concentration gradient across SC, Use formulation techniques to achieve supersaturated concentrations) (2. Alteration of skin barrier by formulation - Can include penetration enhancers, Ointments are greasy and restrict water loss from skin -> stratum corneum become more permeable)
6. Alteration of skin barrier by formulation
7. Skin hydration (Hydrated skin is generally more permeable to drug, Thought to be due to looser packing of SC lipids -> less restrictive path to drug diffusion, Opens up the SC and can increase SC penetration 10-fold)
158
How are glucocorticoids used in skin disorders?
- They target inflammation in skin - psoriasis, eczema, pruritic etc
- Fatty acid esters of active drugs to promote absorption
- Choice of glucocorticoids depends on severity of the disease and location of the disease
- Used in combinations with antimicrobials in infection
MECHANISM OF ACTION: Inhibit release of inflammatory mediators, NF kappa B, neutrophil activation and emigration, mast cell release, immune cell activation.
SIDE EFFECTS:
1. Short term use -> low potency generally safe
2. Prolonged usage can lead to:
- Steroid rebound
- Skin atrophy
- Systemic effects
- Spread of infection
- Steroid rosacea in face
- Stretch marks and superficial dilated blood vessels
159
How are retinoids used in skin disorders?
- Disturbances in vitamin A metabolism disrupt skin
- Retinoic acid has potent effects on skin homeostasis
- Used to treat acne, eczema and psoriasis
- Usually topical application, oral in severe cases.
MECHANISM OF ACTION:
- Bind to RXR and RAR nuclear receptors in keratinocytes and sebaceous glands to decrease cell proliferation and sebum production
SIDE EFFECTS:
- Dry, flaky skin
- Stinging, burning sensation
- Teratogenic
- Joint pains
160
What are some examples of of retinoid drugs?
- Tretinoin
- Isotretinoin
- Alitretinoin
- Tazarotene
- Adapalene
161
How are Vitamin D analogues used in skin disorders?
- Mixture of related substances - Calcitriol - biologically active molecule
- Act via VDR to modulate gene transcription in keratinocytes, fibroblasts, Langerhans cells and sebaceous glands
- Anti-proliferative and pro-differentiative effects in keratinocytes - *psoriasis*
- Inhibit T cell activation
- Given topically usually
- Side effects - possible effects on bone and potential skin irritation
162
Name some main Vitamin D analogues.
- Calcitriol
- Calcipotriol
- Tacalcitol
*Used in psoriasis*
