IRISH DERM TUTOR

Hair introduction

Hair cycle

Scarring vs non-scarring alopecia

Immune privilege

Making a diagnosis

Alopecia areata 

Pathogenesis

Workup

Clinical

Trichoscopy and hair pull test

Histopathology

Associations

Lab investigations

Prognosis

Treatment

Androgenetic alopecia (patterned hair loss)

Below is a schematic of the hair follicle

Of note,

• The dermal papilla is found at the base of the hair follicle. It has a rich blood supply. It contains a collection of mesenchymal cells which play a role in regulating hair growth by interacting with hair matrix cells.

• The hair matrix sits above this and is contains cells responsible for producing the hair shaft. These cells divide and differentiate to from different parts of the hair shaft (eg the cuticle, cortex, medulla)

Normal human hair growth cycle occurs in distinct phases

Anagen phase (active hair with follicular growth):

In a normal scalp 90-95% of hair follicles are in the anagen phase

The matrix cells divide and produce hair cells

These differentiate and move upwards to form the hair shaft

Typically lasts 2-7 years

Catagen phase (regression with follicular involution):

< 1% hair follicles are in this phase

Is a short transition phase (2-3 weeks)

During this phase the follicle beings to shrink and detach from the dermal papilla which provides the hair follicles blood supply

Telogen phase (follicular rest and shedding of hair follicles)

5-10% hair follicles are in this phase

This is the resting phase and usually lasts about 2-4 months

The hair shaft initially remains in place but is no longer growing

Eventually the hair shaft is shed

The follicular unit then switches back into an early anagen phase where hair regrowth begins again

One of the main things to work out when dealing with hair loss is whether this is a scarring alopecia or a non-scarring alopecia

For instance if you get inflammation around the bulb site this results in a non-scarring alopecia (eg alopecia areata)

If you get inflammation at the bulge (around the level where the arrector pili is) then you destroy the follicular stem cells that reside in this area and you get a scarring alopecia (eg Lichen planopilaris, Discoid lupus)

The final concept I would like to mention before discussing different conditions is that of immune privilege

Immune privilege is a status in which the immune system is in a state of non-reactivity to any antigens in order to prevent local tissue destructive reactions

It is charachterised by a number of mechanisms intricately working together to suppress immune attacks on cells

Sites of immune privilege include the brain, testes, anterior chamber eye

The hair follicle is a site of relative immune privilege

The mechanism in the hair follicle to keep this immune privilege include:

• Production of potent immunosupressants locally (eg TGF β1, IL-10)

• Decreased MHC class 1 expression on cells so that (auto) antigens on these cells can’t be shown to cytotoxic CD8 T cells

• Decreased function of antigen presenting cells

A good analogy I heard at a talk at an alopecia study day with the St. John’s Institute Dermacademy was that you can think of immune privilege as like bricks around a hair follicle

You can lose these bricks at any site vertically along the hair follicle and inflammatory cells can then attack at this site

If get an inflammatory response in the bulge you get a scarring alopecia and if you get it at the bulb you get a non-scarring alopcecia

(The level the ‘brick collapse’ may occur at may be in part determined by genetics)

When dealing with a case of hair loss there are a few important considerations to think about

Is it a scarring or non-scarring alopecia?

If it is a non scarring alopecia you might want to think of what location is it in?

• Focal (eg alopecia areata)

• Patterned - occuring in a specific pattern (eg androgenetic alopecia)

• Diffuse - shedding occuring across the scalp (eg telogen effluvium, alopecia areata)

If it is scarring you can classify it based on the nature of the inflammatory infiltrate

• Primarily lympmhocytic - LPP, Lupus

• Primarily neutrophilic - Folliculitis decalvans

• Mixed primary (eg Folliculitis decalvans/LPP overlap)

Hair workup can include:

• History and exam

• Trichoscopy (eg dermoscopy of scalp)

• Hair pull test

• +/- Biopsy

• +/- Lab investigations

Hair pull test:

To evaluate excess hair shedding

Grasp about 40-60 hairs between index finger and thumb and pull gently upwards

Clasically greater than 10 hairs being removed indicates a positive test (although some consider lower amounts a positive test)

Causes of a positive pull test:

• Alopecia areata

• Telogen effluvium

• Anagen effluvium

• Lose anagen syndrome

• +/- Early androgenetic alopecia

Biopsy:

When a biopsy is performed (in particular for a scarring alopecia) you should do two punch biopsies and ask for vertical sectioning (usual type of sectioning) and horizontal sectioning

When the pathologist looks at the horizontal section it looks like they are looking down on top of the hair follicle

It allows for:

Examination of more hair follicles in one biopsy (allows examination of hair follicles at different stages of the hair cycle)

Analysis of hair follicle from top to bottom (eg from epidermis to hair bulb)

Alopecia areata is a chronic immune-mediated form of non-scarring alopecia inflammatory disease which affect the hair follicles

It is the most common immune mediated cause of hair loss worldwide

Onset may be at any age

Any hair-bearing site can be involved

It can be asscociated with autoimmune disorders and in particular atopic dermatitis, thyroid disease and less commonly SLE

Epidemiology:

Lifetime risk 1-2%

Similar rates in males and females

10-20% affected persons have family history of AA

80% of cases occur before 40 years (50% of these cases begin in childhood)

Alopecia totalis - all or nearly all of scalp hair gone

Alopecia universalis - all or nearly all hair from scalp and body gone

In AA there is damage to hair follicles which occur in the anagen phase leading to premature transition to the catagen and telogen phase, then back to a dystrophic anagen phase

During the active disease process, hair follicles are unable to progress past the early anagen phase

Hair follicle stem cells are spared so no hair follicles are destroyed (ie no scarring)

The pathomechansim surrounding AA is complex still not fully understood

It is multi-factorial and involves interactions between immunologic, genetic and environmental factors

Essentially in AA you get loss of follicular immune privilege and an associated T cell-mediated immune attack on cells within the hair bulb

Immune factors:

The main theory of AA pathogenesis is that it develops through the loss of immune priviliged status of hair follicles which leads to the infiltration of inflammatory cells, especially cytotoxic T cells and NK cells, into the hair bulb causing death of follicular keratinocytes

As mentioned above with immune privilege you have:

• Have production of potent immunosuppressants locally

• Get prevention of activation of T cells and NK cells in the area

A potential pathway in alopecia areata is that local stressors (? Trauma, infection, stress, atopy) leads to a stressed hair follicle and decreased expression of the immunosupressive cytokines IL-10 and TGF-beta (‘immune privilege guardians’)

There is now an inflammatory environment with increased pro-inflammatory cytokines such as IFN-gamma and IL-15

• IFN-gamma induces expression of MHC class 1 molecules on keratinocytes making it more susceptible to recognition by cytotoxic T cells

• IL-15 promotes the survival of cytotoxic T cells and NK cells

• IFN-y and IL-15 singal through JAK-STAT signalling (Hence why JAK inhibitors are used in alopecia areata)

Stressed follicular keratinocytes also express more MICA which is a ligand that is normally absent or low on follicular keratinocytes (think of MICA is an alarm to signal stress)

NKG2D is a receptor that is expressed by NK cells and cytotoxic T cells that can bind to MICA

When NKG2D is activated after binding to MICA it acts as a ‘go signal’ for cytotoxic T cells and NK cells to carry out their cytotoxic functions

All the above mechanisms result in cytotoxic T cells and NK cells swarming and attacking the hair bulb causing keratinocyte apoptosis

It is important to know that it is a complicated process and pathogenesis is still not fully known other cells and cytokines that have been associated with pathogenesis include plasmacytoid dendritic cells (pDCs), IL-17, IL-23, TNFa, CCL20, CXCR3, CXCL10 among others.

Genetics:

Genetics also play a role in a patient’s susceptibility to developing alopecia areata

The HLA subtype most associated with alopecia areata are different HLA-DR subtypes and for instance HLA DRB1*11:04 allele can be associated with early onset AA and high familial recurrence risk

Other genes that have been implicated in the development of AA include:

IL2RA (Interleukin-2 receptor alpha)

CTLA4 gene

IL-10 gene

Clinical history and exam

Trichoscopy

Biopsy

Lab investigations

Hair loss is typically asymptomatic but can get occasional pruritus/burning prior to hair loss

Ask about the speed of onset of hair loss

Different patterns of alopecia areata can be observed

Patchy alopecia:

Commonest clinical variant

Smooth, circular, discrete areas of hair loss developing over period of a few weeks

May remain discrete or enlarge and coalesce

Oophiasis pattern:

A band-like area of alopecia extending across occipital scalp

Alopecia totalis:

Total loss of scalp hair

Alopecia universalis:

Loss of all hair over entire skin surface

Diffuse alopecia areata (aka alopecia areata incognita):

Rare form of AA predominantly seen in young women

Get rapidly progressive, generalized thinning of scalp hair

Clinical picture can resemble telogen effluvium but dermoscopic findings may point towards this diagnosis

Prognosis generally quite favourable

Can be used to confirm disease and get indication of disease activity

• See hair follicle orifices (absence suggests a cicatricial alopecia)

• Exclamation point hairs

  • Common and is pathognomic finding in AA

  • Represents acute inflammation to the hair bulb in the anagen phase leading to the hair getting progressively thinned and weak

  • Get short hairs where the proximal end is narrower than distal end

  • Typically found at the edges of expanding patches and can be taken out with minimal traction

• Black dots

  • Seen in acute alopecia areata

  • Represent hair shafts broken off at the level of the skin surface

  • Not exclusive to AA (also seen in trichotillomania, tinea capitis, dissecting cellulitis)

• Yellow dots

  • Seen in chronic alopecia areata

  • Represent an empty hair follicle with a dilated ostium filled with scale and sebum

  • Again is not specific not specific to AA (also seen in androgenetic alopecia, chronic discoid lupus and dissecting cellulitus)

  • Groups of yellow dots typical of AA

Others:

• Short vellus hairs

• Broken hairs

Hair pull test:

Can be useful for confirming active hair loss

Perform if have uncertainty about diagnosis

Take from edge of patch of active hair loss and include a few remaining hairs

Typically do x2 4mm punch biopsies that extend ito subcut fat on scalp

Ask for vertical sectioning of one and horizontal sectioning of the other

The picture you see depends on the stage of the disease

Acute disease:

Get an intense peribulbar, lymphocytic infiltrate surrounding the anagen follicle and the inflammation looks like a ‘swarm of bees’

May see follciluar oedema, cellular necrosis and pigment incontinence

Chronic disease:

Get folllicular miniaturisation

Essentially with time the hair follicles ‘get frightened’ and are converted to telogen hairs

(so see increased proportions of hair follicles in catagen or telogen phase)

By this stage the inflammatory infiltrate is usually less pronounced

May see pigment casts (clumps of melanin within the hair follicle)

You can then get either:

Recovery -reduced inflammation and regrowth of hair

or

Follicular scarring - with long standing inflammation can get permanent loss of hair follicles with only the sebaaceous gland left

Nail Disease:
Seen in 10-20% of AA patients

Nail involvement has been associated with greater severity of disease

It can present in various ways:

• Pitting commonest

• Trachonychia (roughened nail plate)

• Onychorrhexis (longtidudinnal fissuring nail plate)

• Red spotting lunulae

• Onycholysis

• Onychomadesis (detachment of proximal nail plate from nail bed)

Autoimmune associations:

Vitiligo

Thyroid disease

Atopic dermatitis

Lupus erythematosus

Psoriasis

Genetic disorders associated with increased risk of AA:

Trisomy 21

Pyschosocial associations:

Increased mood and anxiety disorders

Often screen all adults and children for autoimmune thyroid disease

Thyroid disease can occur later so new symptoms should prompt checking thyroid tests again

Some propose only screening those at high risk for thyroid disease, ie those with:

Atopy

Trisomy 21

Family history of thyroid disease

Only need to test for other autoimmune diseases if have clinical symptoms or signs suggestive of them

AA can persist for several years or indefinitely

Around 50% with limited patchy hair loss will recover within a year

Approx 66% patients show complete regrowth within 5 years

Unfortunately almost all will experience more than one episode of the disease (85-100% relapse rate over 10 years)

Regrowth sometimes begins with apperance of fine, white vellus hair

Approx 10% of patients with patchy disease progress to alopecia totalis or universalis

If get alopecia totalis - 75% will remain with AT

Cosmetic options:

Can consider if patients don’t want traetment or who have incomplete responses

Wigs

Hairpieces

Sprays, lotions, powders to make hair appear more full

Eyebrow tattoing

False eyelashes

First line therapies:

Limited patchy (generally < 50% scalp affected)

Topical steroids

Intralesional steroids

Intralesional steorids:

Good therapy for adults with with isolated patches of hair loss

Generally people with < 25% hair loss are best candidates as hard to tolerate large number of injections

Beard/eybebrow: use concentrations of 2.5-5mg/ml triamcinolone in upper subcutis

Scalp: can use 5-10mg/ml triamcinolone in upper subcutis

New growth usually visible within 6-8 weeks

May repeat as required every 4-6 weeks and stop once regrowth is complete

If no response at 6 months should discontinue treatment

Method:

Inject 0.1ml or les into multiple sites 1cm apart

Dose per visit determined by extent of disease and toelrance but is usually 20mg or less on scalp

Don’t give more than 40mg per treatment

Adverse effects:

Skin atrophy (usually resolves within few months)

Hypopigmentation (be careful in pigmented skin particularly)

Telangiectasia

(Work in progress)

(Also known as patterned hair loss: eg Female or Male pattern hair loss)

Essentially get a progressive non-scarring miniaturization of hair follicles located in characteristic areas of the scalp in genetically predisposed patients

Male:

Classically get a receding hair line and/or bald spot on vertex of scalp that progressively gets worse over time

Females:

Different than that in men

Get increased hair shedding, diffuse reduction in hair volume or both over the mid-frontal scalp

Women often notice they have less hair on the top of their head and may notice that the scalp is more visible than previously

The size of the ponytail becomes smaller in diameter so a good queestion to ask is:

“If you tie your hair back in a ponytail, how thick is the ponytail compared to 5 or 10 years ago or before you started losing you hair?”

Most common form of alopecia in women

Prevalence in caucasians (lower in Asian population)

3-12% 3rd decade

14-28% 6th decade

29-56% women aged ≥ 70

Complex polygenetic aetiology involving several genes involved in androgen or oestrogen activity

Pathogenesis is not identical in male and female pattern hair loss

Androgen binding to hair follicle androgen receptors is important in the pathogenesis

Most women with FPHL have an increased sensitivity of the hair follicle to normal androgen levels (although sometimes FPHL can occur unrelated to androgen status)

Increased androgen sensitivity leads to miniaturization of hair follicles over time with progressive transition of terminal to vellus hairs

• Hair is shorter, thinner and paler

• Get diameter variability between different hairs

Women also get shortening of the anagen phase with premature catagen entry

All these factors lead to the phenotype of FPHL