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1

What are the layers of the skin

Dermatology
Structure of the Skin

Largest organ in the body: composed of epidermis & dermis overlying subcutaneous tissue.

2

Describe the epidermis

Includes keratinocytes (produce keratin), Langerhan’s cells (present antigens & activate T lymphocytes), melanocytes (produce melanin) & Merkel cells (contain specialised nerve endings)

The 4 layers of the epidermis are:
- stratum basale (basal cell layer)
- stratum spinosum (prickle cell layer)
- stratum granulosum (granular cell layer)
- stratum corneum (horny layer)

In areas of thick skin (e.g. sole): stratum lucidum (beneath stratum corneum). Consists of paler, compact keratin.

As cells move up through the epidermis, keratin content increases from 35% > 80% (keratin intermediate filaments). In the basal cell layer: K5 (basic) & K14 (acidic). In the supra-basal layer (i.e. spinosum): K1 (basic) & K10 (acidic). The average epithelial turnover time (migration of cells from basal cell layer  horny layer) is ~30 days.

The basal cell layer contains actively dividing cells (stem cells most likely in hair follicles, but transient amplifying cells in basal layer where cell division occurs). This forces daughter cells up  next layer. The prickle cell layer contains differentiating cells. The granular cell layer contains cells that lose their nuclei (differentiation) & granules of keratohyaline. Lipids are secreted into the intracellular spaces. The stratum corneum is a superficial layer of keratin.

3

What pathology can affect epidermis

Changes in turnover time (e.g. psoriasis), changes in surface of the skin / loss of epidermis (e.g. scales, crusting, exudate, ulcer), changes in pigmentation.

4

Describe the dermis

Consists of collagen, elastin _ glycosaminoglycans (and fibroblasts which are responsible for synthesis).

Immune cells, nerves & sensory receptors, skin appendages / sweat glands, lymphatic & blood vessels are also found in the dermis.

The dermis is responsible for perfusion of the epidermis (blood vessels stop at the dermis).

5

What pathology can affect the dermis?

Changes in contour of skin / loss of dermis (e.g. papules, nodules, skin atrophy, ulcers), disorders of appendages (e.g. hair disorders, acne), lymphatic or blood vessel changes (e.g. erythema, urticaria, purpura).

6

Functions of the skin?

Protective:
1. Sensory, renewal & repair.
2. Impermeability to chemicals & water.
3. Resistance to microbial penetration.
4. Immune defence.
5. Protection against UV damage.

Renewal & Repair (protection against injury, wear & tear)
- Keratin intermediate filaments form pairs to act as support: (K5 + K14 in basal layer, K1 + K10 in suprabasal). Likely to be because basal layer requires more ‘bendy’ keratins that force daughter cells into next layer & more protection required in more superficial regions therefore become more rigid.
- Continued renewal of the epidermis

7

What are the 4 stages of wound healing?

Haemostasis, inflammation, proliferation + remodelling.

Haemostasis = vasoconstriction + platelet aggregation, clot formation.

Inflammation = vasodilation, migration of neutrophils & macrophages, phagocytosis of invading debris / bacteria

Proliferation = granulation tissue formation (synthesis by fibroblasts) & angiogenesis. Re-epithelialisation by epidermal cell proliferation & migration. In response to wounding basal cells recognise gap divide to cover wound. Basal cells over the wound then fill in the higher epidermal layers through differentiation with daughter cells moving upwards.

Remodelling = collagen fibre reorganisation & scar maturation

- Role of collagen VII (see epidermolysis bullosa dystrophica).

8

Why is the skin impermeable?

STRATUM CORNEUM: very thin barrier, easily damaged: keeps fluids, electrolytes, microbes + chemicals out (also prevents medicine penetration – e.g. ~10% steroids will penetrate skin; drugs e.g. cyclosporine + methotrexate must be given orally).

- Consists of corneocytes with fat between the cells. Keratinocytes differentiate + lose nucleus as they move up through epidermis + filaggrin-mediated aggregation of keratin filaments into kerato-hyaline granules occurs. Keratin aggregates fuse with cell envelope (corneocyte proteins which are cross-linked & insoluble). Intracellular lipids are secreted from lamellar bodies (lipids fill gaps between corneocytes).

- Filaggrin binds the keratin filaments into sheaths: many people with atopic eczema have a mutation in filaggrin > defective barrier > pollens/grasses/dust mite can penetrate skin + trigger immune system.

9

What is the immune defence of the skin?

- Langerhans cell is one example of an antigen presenting cell in epidermis – part of ‘innate’ immune defence. When exposed to perturbation (antigen etc) the skin produces cytokines which cause Langerhans cells to migrate down to dermis + to draining lymph node > initiate immune response to antigen.

Stimulus could be infection, cytokine, irritant or even UV.

Darker staining cells = Langerhans cells (can see migration downward).

UV has a suppressive action when the Langerhans cells migrate down, whereas irritants activate the immune system.

10

Outline the skins protection from UV

More melanin pigment produced by melanocytes (dendritic cells that synthesis melanin in small organelles called melanosomes) in response to UV exposure.

Melanocytes mature > pass melanin on to keratinocytes

Keratinocytes takes up melanin and use it for protection.

Number of melanocytes similar across different human pigmentary groups (and all humans have more in facial/genital areas). But changes in genes mean some melanocytes produce less melanin pigment than others across different people.

UV energy taken up by bases in our DNA > covalent bonds form between adjacent bases. (CPD = two bonds, 6-4PP = one bond: 6-4PP).

25-30 proteins exist that travel along the DNA looking for damage > recruits helicases that unwind DNA > restriction (excision) enzymes cut out damage > DNA polymerase synthesis new repaired strand (using opposite strand as template) > ligation by DNA ligase. This is known as nucleotide excision repair.

Excision proteins are known as ‘XP’ proteins because they are responsible for xeroderma pigementosun. If born with both mutated copies, can no longer repair DNA in response to sun damage – could lead to melanoma or squamous cell carcinoma before age 10! Must stay indoors at all times or use NASA space suit outdoors. Or summer camps where go out in middle of night and sleep in the morning.


Prolonged sunbathing episode  so much damage that system overwhelmed. Certain about of damage that is not repaired  mutations. Clones of mutated cells  p53 patch (thought to have potential for future skin cancers). Recent paper showed that normal eyelid skin had cancer causing mutations in about ¼ of cells!

Skin cancer most common in the world (about ½ of all cancers in USA). 250,000 in UK – estimated to double/triple every 10 years.

UV light also suppresses the immune system  increased cancer risk. Migration of Langerhan’s cells downwards to lymph node  signal to produce regulatory T cells that suppress immune responses!

T cell exhaustion also possible – T cells around cancer but not able to recognise it.

11

Homeostasis role of skin?


Homeostasis:
1. Thermoregulation.
2. Endocrine: vitamin D3 production.

Thermoregulation

Vascular heat exchange: switch on vessels to release heat or close off to conserve heat. Also controls sweating. If this system goes wrong > erythroderma.


12

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Types of Skin Cell (deep > superficial)

Subcutaneous fat, vessels + nerves, adnexal glands (sweat, sebaceous), fibroblasts in dermis, melanocytes, basal cell keratinocytes, squamous cell keratinocytes. Any cell type may give rise to a tumour.

Skin lesion history: how long, changes, single or multiple, any previous Hx, sun/tanning bed exposure, painful or tender to touch, bleeding/scabbing, tender to touch? Rate of growth?

Inspection: describe lesion, dimensions in mm (ruler), location (e.g. 2cm anterior to left ear), flat / depressed / elevated / mixed. Colour: even or mixed. Edge: even or irregular. Surface: scab, scale, keratin, ulcer.

Palpation: impalpable (flat)? Does tensioning skin change appearance (e.g. BCC)? Does it dimple on bidigital palpation (dermatofibroma). Is it tender? (e.g. SCCs).

Note: soft lesions usually harmless.

Benign Skin Lesions

Moles (melanocytic naevi)
• Normally emerge & change during the first 2 decades. Develop and mature during life (emerge, enlarge, elevate, lose colour, regression). Facial naevi tend to become elevated and lose colour in age (intradermal naevi).
• May be flat, elevated, or compound naevi.
• Not all pigmented lesions are melanocytic, and not all melanocytic naevi are pigmented!
• Individuals tend to have a particular type (therefore compare to rest of body)
• Blue naevi: typically appear ~20; ankles/wrist/head – must be small & stable (<6mm).
• Naevus spilus: usually 3-4cm
• Halo naevus: usually age 8-25,
• Average adult has 40 or 50 naevi. Atypical mole syndrome: higher risk of melanoma – 100+ moles with at least 2 >5mm and slightly irregular
• Darker skin = darker moles (and vice versa)
• Malignancy rare <16 and in darker skin
o Don’t worry about mildly atypical, new or slowly changing naevi in someone <25, worry if >40.
• Note: naevi on the foot are no more likely to be malignant than elsewhere!

Types of benign melanocytic lesion

• Acquired
o Lentigo simplex (benign lentigo) or freckle (small flat layer of melanocytes)
o Junctional naevus (slightly thicker – dermo-epidermal junction)
o Intradermal naevus (thicker; normal melanocytes descending into dermis)
o Compound naevus (junctional & intradermal elements)

• Congenital: very low risk of becoming melanoma.
o Bathing trunk naevus high risk (1/2-1/3 of body) but these are extremely rare.



Warts (viral & non viral)

Haemangiomas

Dermatofibromas

Cysts

Lipomas

Rare things…

ACANTHOSIS NIGRICANS



13

Symptoms and signs of psoriasis and types?

Signs: erythematous plaques (red and goes white when pressure applied) – well demarcated
- Scaling, variable size
- Any site but often extensors
- Pustules (rare)

Subtypes:
- Chronic plaque (most common)
- Guttate (tear drop: often young adult / late teens with sore throat > UV therapy helps but ~50% evolve into chronic plaque psoriasis)
- Flexural (usually not treated by rule of 10)
- Erythroderma (can also be caused by other diseases – not just psoriasis)
- Pustular: may be generalised pustular psoriasis (serious – requires hospitalisation) or palmoplantar (about 25% with this will also have chronic plaque psoriasis) – not worrying but difficult to treat

Nails: affects 30-50%, several affected
- Pitting
- Onycholysis
- +/- Paronychial psoriasis

14

Psoriasis complications?

Associated diseases?

Joints / Psoriatic arthropathy
- Affects up to 25%
- Seronegative
- 5 types
o Mono / oligoarthropathy
o Distal interphalangeal
o Rheumatoid-like (but negative for RF)
o Anklyosing spondylitis (loss of lumbar lordosis, thorqcic kyphosis etc).
o Arthritis mutilans (opera glass): erosions of joints then erosions into bones  end stage disease that you don’t want to reach).

Associations
- Obesity
- Increased cardiac mortality
- Diabetes mellitus
- Metabolic syndrome
- Crohn’s (12% with Crohn’s)

15

Aetiology / pathogenesis of psoriasis?

Chronic relapsing condition: 2-4.5% of Europeans. M=F.

Onset any age: Type I psoriasis: 10-30 yrs, Type II >40 yrs
If found in late teens and not cleared immediately, likely to persist into old age. High social impact.

Genetic predisposition: Fhx common, 35-73% concordance monozygotic twins, polygenic disease
- HLA-C on chromosome 6 (50% susceptibility)
- Modifier genes (cytokines e.g. VEGF): more severe disease if VEGF mutation > affects blood vessels (plaques)
- HLA-B27 psoriatic arthropathy

Environmental exacerbations
- Infections: streptococcus
- Drugs: lithium + most likely beta blockers(?), alcohol
- (?) Stress (neuropeptides) / hormonal
- Koebner phenomenon (due to scratching): note; treatment with UV could cause damage and therefore cause more psoriasis!

Pathogenesis
- Hyperproliferative: increased mitosis in the lower epidermis, lower transit time (reduced from 30 > 4 days).
- Immunological: therapy (cyclosporin, anti-IL-17 etc.), cytokine alterations
- Angiogenesis: increased vessel growth (VEGF)

Epidermis: hyperkeratosis (scaling), acanthosis / elongated Rete ridges (move doen into tissue as finger-like projections), neutrophil invasion, increased mitosis.

Dermis: papillary vessels dilated, lymphocytic infiltrate

16

Treatment of psoriasis?

Topical > UV > Systemic

Topical Treatment (dithranol, tar, vit D analogues, vit A analogues, steroids)

UV Treatment

Systemic Treatment (severe cases): rule of 10s

Rules of tens
1. Psoriasis area and severity index (PASI): redness, scaling, induration and surface area (>10)
2. Dermatology life quality index (DLQI): how does it affect you (>10)
3. Body Surface Area (BSA): not used clinically but can explain to patients about when systemic treatment justified (10%),

Methotrexate: weekly dose (low dose: 5-20mg)  liver fibrosis (check for cirrhosis)
Cyclosporin: renal, BP, maximum 1 year therapy ( skin cancers if longer)
Acitretin: raised lipids, teratogenic (only one that is not immunosuppressive, most likely works through blood vessels / keratinocytes)
Azathioprine: FBC, LFTs
Hydroxycarbamide: FBC

Others (Mycophenolate mofetil, Fumaderm) – not included by NICE…

Biologics (Adalimumab, Etanercept, Infliximab, Ustekinumab, Secukinumab):
- Adalimumab, Entanercept & Infliximab = anti-TNFa, side effects = reactivation of TB, soft tissue infections, possible link with lupus, GB, MS.
- Ustekinumab = anti - IL-23 (causes T cell activation)
- Secukinumab = anti - IL-17 (T cell activation causes  IL-17)

Note: never use oral steroids

Assessment of disease severity
- Resistance to therapy
- Rapid spread
- Surface area
- Systemic features (shivery)
- Tender, dark red plaques
- Type of psoriasis
- Treatment history


Wizbit.net/dermdiag

Guest. ddtest

Pemphigus Vulgaris

Vitamin
Bullous Pemphigoid

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History And Examination of Skin

History
- How long
- Related to anything (sun, contact, food – less common)
o If food allergy e.g. shellfish would see immediately after eating
- Constant / variable
- Itch
o Uritcaria: Lesions come & go over 24 hour period (mast cells release histamine: can only release a set amount). Draw around lesion (wheal) & observe next day.
- Past History
o Atopy (childhood eczema, asthma, hay fever), drug history, other medical complaints
- Family history
o Genetic disease or contagious (scabies, impetigo)
- Social history
o Occupation & chemical exposure (especially hand dermatitis e.g. hairdressing, better at weekends / holidays)
o Sun exposure: lived abroad / frequqnt holidays

Skin types

Previous treatments: ointment or cream, steroid/fungal/biotic – help or worsened?
Drug rashes: usually widespread, occur within frist 2 months usually

Look, feel, describe

Look: sites, distribution, arrangement of lesions
- Distribution: symmetrical (endogenous) or asymmetrical (exogenous)
o Asymmetry: tinea (ringworm), impetigo
o Symmetrical: atopic eczema (face & flexures), psoriasis (extensors: elbows/knees)

- Arrangement; annular, linear or grouped (insect bites – normal skin between lesions).
o Discrete vs coalescent

Palpation: surface (use finger tips), deep (compress with finger & thumb), scratch & pick
- Surface: smooth, uneven, rough
- Deep: soft, normal or firm (e.g. keloid scar)

Describe: 1. Size & Shape / site 2. Raised/depressed 3. Surface 4. Colour 5. Border

Types of lesion: flat, raised, fluid filled, broken surface

Difference between nodule & plaque: nodule can be squeezed (substance), plaque has no substance but can feel elevation if move hand over surface
- Plaques mainly psoriasis
- Coalescing papules can also be described as plaques (but not primary plaques)
- Vesicles = blisters, larger vesicles = bullae (e.g. shingles – always unilateral).
- Large pustule = abscess
- Erosion = loss of epidermis
o Two causes of erosions = TRAUMA or BLISTERS
o Two depths: intra-epidermal, subepidermal
o Small erosions = within papule or plaque
o Eczema: blisters erosions an exudate (eczema is most common blistering disease)

Ulcer = loss of the dermis




Can contract chicken pox from shingles if not immune.


Surface Features

SCC much more nodular than BCC and grow faster

Leichenification: most commonly seen in atopic eczema


Melanin pigmentation (hyperpigmentation on dark skin) = erythema

Haemodisderin pigmentation (purpura – blood leaking out of vessels – reabsorbed and iron pigment left behind as haemosiderin – more rusty orange rather than the brown of melanin)

Hypopigmentation: Vitiligo = autoimmune – attacks pigment cells

Partial hypopigmentation: can also occur with inflammation (must be quite severe inflammation to cause hypo as opposed to hyperpigmentation)

Also caused by reduced blood supply – shunting

Border
- Well defined
- Poorly defined
- Accentuated


17

Treatment of psoriasis?

Topical > UV > Systemic

Topical Treatment (dithranol, tar, vit D analogues, vit A analogues, steroids)

UV Treatment

Systemic Treatment (severe cases): rule of 10s - methotrexate, cyclosporin, acitretin, azathioprine, hydroxycarbamide. Others (mycophenolate, mofetil, Fumaderm - not included by NICE...)

Biologics: Adalimumab, Etanercept, Infliximab, Ustekinumab, Secukinumab

18

Outline topical psoriasis treatments

1. Dithranol (dithrocream 0.1-2%): short contact, clears ~70% > staining / can burn

2. Tar: very effective (Exorex, psoriderm, carbo-dome). Clears ~70% > Folliculitis

3. Vit D analogues
- Calcipotriol (Dovonex) clears ~40%
- Tacalcitriol (Curatoderm)
- Calcitriol (Silkis)

4. Vit A analogues
- Tazarotene (Zorac) clears ~40%  Irritation

5. Steroids
- No remission, flexural psoriasis

Vitamin analogues easier to use / don’t stain skin – most patients prefer to start with them.
- If use tar: clear for a few month before it comes back
- If use topical steroids: no remission period – if stop using comes back immediately

Combination calcipotriol + steroid (1 month): then change. But studies suggesting that after 8 weeks: still improved to same extent regardless of whether steroid is added (i.e. steroid gets you to the point quicker but of no benefit afterwards).

19

Outline UV treatment for psoriasis

UV Treatment: lots of factors to consider e.g. size of patient (obesity etc.). Not appropriate for everyone.

UVB: Narrow band / broad band (broad has all UBV wavelengths whereas narrow band only ~370nm: optimum wavelength according to a paper so predominantly used) 3x week. Risk of skin cancer (sqamous, not melanoma). Can burn: test minimal erythema dose.

PUVA: (UVA): oral / topical 8-methoxypsoralen used. 2x week. PUVA keratosis, freckles. Skin cancer, especially squamous cell carcinoma. Can burn: test minimal phototoxic dose. Not used as much due to burn risk. Lasers also occasionally used for small areas (can be bought).?

20

How is psoriasis assessed

Rule of 10s: current severe psoriasis

1. Psoriasis area and severity index (PASI): redness, scaling, induration and surface area (>10)

2. Dermatology life quality index (DLQI): how does it affect you (>10)

3. Body Surface Area (BSA): not used clinically but can explain to patients about when systemic treatment justified (10%),

Assessment of disease severity
- Resistance to therapy
- Rapid spread
- Surface area
- Systemic features (shivery)
- Tender, dark red plaques
- Type of psoriasis
- Treatment history

21

Outline systemic therapies for psoriasis

Methotrexate 1st line: weekly dose (low dose: 5-20mg) > liver fibrosis (check for cirrhosis)

Cyclosporin: renal, BP, maximum 1 year therapy ( skin cancers if longer)

Retinoids / Vit A: e.g. acitretin: raised lipids, teratogenic (only one that is not immunosuppressive, most likely works through blood vessels / keratinocytes)

Azathioprine: FBC, LFTs

Hydroxycarbamide: FBC

Others (Mycophenolate mofetil, Fumaderm) – not included by NICE…

Biologics - early trials. (Adalimumab, Etanercept, Infliximab, Ustekinumab, Secukinumab):

- Adalimumab, Entanercept + Infliximab = anti-TNFa, side effects = reactivation of TB, soft tissue infections, possible link with lupus, GB, MS.

- Ustekinumab = anti - IL-23 (causes T cell activation)
- Secukinumab = anti - IL-17 (T cell activation causes  IL-17)

Note: never use oral steroids

22

NICE: management of chronic plaque psoriasis

Regular emollients may help to reduce scale loss and reduce pruritus

1st: Potent corticosteroid 1x day + Vit D analogue 1x day (applied separately, one in morning and other in the evening) for up to 4 weeks as initial Tx

2nd line: if no improvement after 8 weeks, offer Vit D analogue 2x day

3rd line: if no improvement after 8-12 weeks, offer either: potent corticosteroid 2x daily up to 4 weeks or coal tar prep 1-2x day. Short-acting dithranol can also be used.

23

Use of steroids in psoriasis (side effects)

Use of vitamin D analogues in psoriasis?

Topical steroids: skin atrophy, striae and rebound symptoms. Scalp, face and flexures are particularly prone to steroid atrophy so topical steroids should not be used for more than 1-2 weeks/month Commonly used in flexural psoriasis and also a role for mild steroids in facial psoriasis. If steroids are ineffective for these conditions vitamin D analogues or tacrolimus ointment should be used second line.

Systemic side-effects may be seen when potent corticosteroids are used on large areas e.g. > 10% of the body surface area.

NICE recommend aim for 4 week break before starting another course of topical corticosteroids. Also recommend using potent corticosteroids for no longer than 8 weeks at a time and very potent corticosteroids for no longer than 4 weeks at a time.

Vitamin D analogues include: calcipotriol (Dovonex), calcitriol and tacalcitol - reduce cell division and differentiation. Adverse effects are uncommon- may be used long-term

Unlike coal tar and dithranol they do not smell or stain, tend to reduce the scale and thickness of plaques but not the erythema - should be avoided in pregnancy
Maximum weekly amount for adults is 100g

24

Steroids for scalp / face / flexural / genital psoriasis?

Scalp psoriasis
NICE recommend the use of potent topical corticosteroids used once daily for 4 weeks
if no improvement after 4 weeks then either use a different formulation of the potent corticosteroid (for example, a shampoo or mousse) and/or a topical agents to remove adherent scale (for example, agents containing salicylic acid, emollients and oils) before application of the potent corticosteroid

Face, flexural and genital psoriasis
NICE recommend offering a mild or moderate potency corticosteroid applied once or twice daily for a maximum of 2 weeks

25

Steroids for scalp / face / flexural / genital psoriasis?

Scalp psoriasis
NICE recommend the use of potent topical corticosteroids used once daily for 4 weeks
if no improvement after 4 weeks then either use a different formulation of the potent corticosteroid (for example, a shampoo or mousse) and/or a topical agents to remove adherent scale (for example, agents containing salicylic acid, emollients and oils) before application of the potent corticosteroid

Face, flexural and genital psoriasis
NICE recommend offering a mild or moderate potency corticosteroid applied once or twice daily for a maximum of 2 weeks

26

??

Mechanism of action of commonly used drugs:
coal tar: probably inhibit DNA synthesis
calcipotriol: vitamin D analogue which reduces epidermal proliferation and restores a normal horny layer
dithranol: inhibits DNA synthesis, wash off after 30 mins, SE: burning, staining