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ALOPECIA AREATA AND RECENT ADVANCES By : Dr. Ajeet Singh

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Page 1: Alopecia areata and recent advances

ALOPECIA AREATA AND

RECENT ADVANCES

By : Dr. Ajeet Singh

Page 2: Alopecia areata and recent advances

ALOPECIA originates from Greek word “alopekia”

meaning “fox mange” or disease with hair loss in foxes.

Definition – • Alopecia areata is a common, chronic, inflammatory

disease that causes non scarring hair loss. ‐

• Severity ranges from small patches to complete

alopecia.

Page 3: Alopecia areata and recent advances

HISTORY OF ALOPECIA AREATA

• 1st description of alopecia areata - Celsus.

• 1st used the term alopecia areata - Sauvages (1763)

• 1st to suggest that alopecia areata is an auto immune disease - Rothman.

Page 4: Alopecia areata and recent advances

EPIDEMIOLOGY• Prevalence worldwide - 0.2%

• Estimated lifetime risk - 1.7%.

• Incidence in india – 0.7% of new dermatology cases.

• Male = Female

• Age group affected – All age groups

20% of cases are children

60% has 1st patch before age 20 yrs.

• Familial occurrence - 15%.

• Alopecia totalis - 5% of patients

• Alopecia universalis - 1% of patients

Page 5: Alopecia areata and recent advances

CLASSIFICATION OF ALOPECIA AREATA

• Based on pattern of alopecia.

• Based on Ikeda types.

Based on pattern of alopecia –

1. Generalised – Alopecia universalis

2. Restricted to scalp – Patchy

Ophiasis/Sisaphio

Reticulate

Diffuse

Subtotal

Alopecia totalis

Page 6: Alopecia areata and recent advances

Ikeda classified AA in four types :

1. Common type – most common type

(81%) fast progression, no patch last ˃ 6 months

affect adults b/w 20 – 40 yrs of age

5 – 15% progress to AT

2. Atopic type – begins during childhood and progresses slowly

(10%) ophiasis and reticular pattern more common

30-75% develop total alopecia

3. Prehypertension type - parental hypertension, reticular pattern most common

(4%) progress is fast, 40% develop AT

4. Autoimmune type – affects middle age

(5%) prolonged course, a/w autoimmune diseases

10-50% develop alopecia totalis

Page 7: Alopecia areata and recent advances

Multifactorial etiology of alopecia areata

Page 8: Alopecia areata and recent advances

Pathophysiology Alopecia areata is an autoimmune disease supported by:

• Increased frequency of other autoimmune diseases.

• Increased frequency of organ specific autoantibodies. ‐

• Serum antibodies to hair follicle tissue also occur with increased

frequency.

• Infiltration of hair bulbs by activated T lymphocytes.‐

• Genetic associations with several autoimmune diseases,

particularly with genes of MHC.

Page 9: Alopecia areata and recent advances

Etiopathogenesis

• A viral etiology was proposed in the late 1970s.

• A genetic study by Yang et al. found that 8.4% of the

patients had a positive family history of AA,

suggesting a polygenic mode of inheritance.

• AA is an organ-specific autoimmune disease with

genetic predisposition and an environmental trigger

(present consensus).

Page 10: Alopecia areata and recent advances

Hypothesis for alopecia areata development

• Current hypothesis - Hair follicle immune privilege collapse.

Inappropriate presentation of antigens to

the immune system during normal hair cycle

• Anagen stage hair follicles retain immune privilege, and a breach

in immune privilege and exposure of unique hair follicle antigens

may result in targeting by the skin immune system.

Page 11: Alopecia areata and recent advances

Table 1: The mechanism of HF immune privilege.

(i) Absent or barely detectable expression of MHC class I.

(ii) Hair follicular melanocytes of the human anagen scalp areMHC class I-negative.

(iii) Downregulation of the MHC class I pathway-relatedmolecules 2-microglobulin and transportation of antigen𝛽processing-2 (TAP-2).

(iv) Downregulation of interferon regulatory factor-1 expression.

(v) Upregulation of immunosuppressive factors such as TGF- 1𝛽and TGF- 2, ACTH, and -MSH.𝛽 𝛼(vi) Absence of MHC class II+ or NLDC-145+ Langerhans cells.

(vii) Sparse distribution of NK cells and CD4+ and CD8+ T cells.

(viii) Absence of lymphatics.

Page 12: Alopecia areata and recent advances

The pathogenesis of alopecia areata

Page 13: Alopecia areata and recent advances

• An alternative hypothesis is based on the knowledge that hair

follicle immunoprotection is transient, limited to the anagen

growth cycle stage.

• Regression of the hair follicle in catagen involves significant

apoptosis and immune cell infiltration.

• This normal hair follicle cycling event may continuously expose

the immune system to low levels of hair follicle derived

antigens.

Page 14: Alopecia areata and recent advances

Fig - Alopecia areata pathogenesis. Inappropriate excitation of antigen presenting cells during disordered catagen and migration of cells to draining lymph nodes may lead to hair follicle antigen specific lymphocyte activation, migration, and infiltration of anagen stage hair follicles.

Page 15: Alopecia areata and recent advances

Hair follicle growth cycling modulation in alopecia areata

There are three key phases of the hair cycle:

1. The growth phase (anagen),

2. The regression phase (catagen),

3. The resting phase (telogen).

• The disruption of these finely tuned pathways can result in the

development of hair diseases.

• Exogen - Controlled shedding of club hair fibers.

• In the development of AA, exogen occurs in advance of

renewed anagen growth, leaving a hair follicle devoid of visible

hair fiber—a state called kenogen

Page 16: Alopecia areata and recent advances

There are several possible presentations of AA.

1. First, the anagen phase inflammation lead to dystrophic

anagen state unable to produce hair fiber of significant size or

integrity.

2. When there is a greater intensity of inflammation, the hair

follicles may be forced into a telogen phase and may then cycle

through multiple anagen telogen phases of brief duration.

3. Finally, when AA is chronic, the hair follicles tend to persist in a

prolonged telogen phase without an apparent attempt to

return to an anagen phase.

Page 17: Alopecia areata and recent advances
Page 18: Alopecia areata and recent advances

Animal models of alopecia areata

Two inbred rodent models have been developed for use in AA

research:

1. Dundee experimental bald rat (DEBR)

2. C3H/HeJ mouse.

• Histology of the skin of mice and rats –

Infiltration of CD4 and CD8 T cells, macrophages, and dendritic

cells in and around the hair follicles.

Page 19: Alopecia areata and recent advances

• AA can be transferred from spontaneously affected mice to

healthy mice with an almost 100% success rate by using a skin

grafting technique.

• The grafting of affected skin promotes an induction of anagen

stage hair follicle inflammation in a skin graft recipient.

• Subcutaneous injection of lymphocyte cell subsets isolated

from AA affected mice into normal mice shows that these cells

induce the disease.

• CD8 cells quickly induced localized patches of hair loss.

Page 20: Alopecia areata and recent advances

When AA affected mouse skin is grafted to severe combined

immunodeficient (SCID) mice:

• Absence of CD4 and CD8 T cells

• Hair regrowth is observed in grafted skin

• No loss of hair is observed in the host skin.

This is a strong indication that CD4 and CD8 T cells are directly

involved in the hair loss promotion mechanism.

Further, partial restoration of hair growth is observed by

depleting CD4 or CD8 T cell subsets by using monoclonal

antibodies in AA affected mice.

Page 21: Alopecia areata and recent advances

Role of genetics in alopecia areata

• Positive family history - 10% to 20% of cases

• Lifetime risk of AA in the children of a proband is - 6%.

• Monozygotic twins: concordance rate of 55%.

AA in twins can have similar times

of onset and patterns of hair loss.

• Strong family history in some patients that spans many

generations.

• Between 4% and 28% of patients who have AA will have at least

one other affected family member.

Page 22: Alopecia areata and recent advances

• Gene association studies have indicated that human leukocyte

antigen (HLA) genes play a role in AA.

• Aberrant expression of HLA antigens found within the follicles

of AA affected patients.

• HLA class II alleles has stronger & much more consistent

association with AA development.

• Specific alleles DQB1*03 and DRB1*1104 - markers for

susceptibility to AA.

• Intervals on human chromosomes 6, 10, 16, and 18 were

identified as potential AA susceptibility loci.

Page 23: Alopecia areata and recent advances

• Genome wide association studies are revealing new

molecular pathways disrupted in AA including autophagy,

apoptosis, TGF β/Tregs and JAK (Janus family of non-receptor

protein tyrosine kinase) signalling. (Petukhova et al).

• Now it is assumed that CD8+ NKG2D+ T effector memory cells

mediate AA in part through Janus kinase (JAK) signaling. The

involvement of IFN γ and the γ C cytokines (IL 2, IL 7, IL 15, ‐ ‐ ‐ ‐ ‐IL 21) suggests downstream signalling via the JAK pathway ‐and that alopecia areata might be treated with JAK inhibitors.

Page 24: Alopecia areata and recent advances

Environmental impact on alopecia areata

Specific gene alleles might provide an innate degree of

susceptibility to AA for an individual, but environmental factors

likely cumulatively determine :

• Actual onset,

• Hair loss pattern, and

• Severity of the disease.

Possible triggers for AA :

1. Hormonal fluctuation,

2. Infectious agents,

3. Vaccinations.

Page 25: Alopecia areata and recent advances

In the mouse model, dietary soy oil increases resistance to AA

development, suggesting that diet might also play a role in AA.

Stress considered a cause for AA onset, but controlled clinical

studies have been inconclusive.

In contrast, several studies have shown that individuals with

AA are more likely to exhibit -

• Increased anxiety,

• Depression, and

• Aggression.

Page 26: Alopecia areata and recent advances

Macrophage migration inhibitory factor (MIF)

• MIF - A cytokine having role in the regulation of macrophage

function.

• It also initiates inflammation and immune response by regulating

a number of proinflammatory cytokines.

• Mean MIF levels in serum and skin were significantly higher in AA

patients than in controls. Mean serum and skin MIF levels were

also found to be higher in severe AA than in mild AA.

• These findings indicate its possible involvement in the

pathogenesis of the disease.

Page 27: Alopecia areata and recent advances

DRUG INDUCED ALOPECIA AREATA

1. Acitretin induced AA – Case reported by Ozlu et al in 2015.

2. AA is common with antipsoriatic treatment. Eg. – Infliximab,

Etanercept, Adalimumab, Elefacept & Efalizumab

3. Vandetanib induced AA – In medullary cancer of thyroid,

reported by Jalalat et al.

Page 28: Alopecia areata and recent advances

CLINICAL FEATURES

• A circumscribed, hairless, smooth patch.

• Skin within the bald patch appears normal or slightly reddened.

• Solitary lesions (Alopecia Areata monolocularis).

• Numerous lesions (Alopecia Areata multilocularis).

• Distinct border - normal hair demarcates the periphery of the

lesion.

• Exclamation mark hairs - are often seen at the margins of the

bald patches during active phases of the disease.

• Free ends of exclamation hairs are splayed giving a frayed rope

appearance on hand lens.

Page 29: Alopecia areata and recent advances

Patch of alopecia areata showing broken ‘exclamation mark hairs’ towards the margins

Close up of exclamation mark hairs‐

Page 30: Alopecia areata and recent advances

• Subsequent course is unpredictable.

• The initial patch may regrow hair within a few months, or

further patches may appear after varying intervals.

• A succession of discrete patches may coalesce to give large

areas of hair loss.

• In some cases, this progresses to a total loss of scalp hair

(alopecia totalis) or a loss of all hair on the body (alopecia

universalis).

• The scalp is the 1st affected site in most cases, but any hair

bearing skin can be affected.

Page 31: Alopecia areata and recent advances

Alopecia totalis with a 100% loss of scalp hair

Alopecia universalis

Page 32: Alopecia areata and recent advances

The ophiasis pattern refers to a severe form of AA extending

along the posterior occipital and temporal scalp margins.

Ophiasis inversus (sisaipho), a rare variant that can mimic male pattern hair loss. Ophiasis pattern

Page 33: Alopecia areata and recent advances

• An intriguing feature of alopecia areata is the sparing of

white hairs.

• Dramatic change in hair colour if the alopecia progresses

rapidly, and leads to people ‘going white overnight’

(canites subita).

• Sparing of white hair is a relative phenomenon and it is clear

that the white hairs, although less susceptible to the disease,

are not immune.

Page 34: Alopecia areata and recent advances

Sparing of white hairs in a patch of alopecia areata

Regrowth of hypopigmented hair in alopecia areata.

Page 35: Alopecia areata and recent advances

Nail changesNail involvement - 7% to 66%.

Classically, alopecia areata causes:

1. Fine stippled pitting of the nails (sandpaper nails)

2. Less well defined roughening of the nail plate (trachyonychia) ‐3. Non specific atrophic dystrophy‐4. Beau lines

5. Onychorrhexis

6. Thinning or thickening, onychomadesis, koilonychia.

7. Punctuate or transverse leukonychia

8. Red spotted lunulae.

Page 36: Alopecia areata and recent advances

Figure An organized pattern of pitting

Nails can be affected before, concurrent with, or after the

resolution of hair loss. Several studies have suggested that nail

abnormalities are associated with more extensive hair loss.

Page 37: Alopecia areata and recent advances

DIFFERENTIAL DIAGNOSIS

Temporal triangular alopecia

Tinea capitis

Trichotillomania

Telogen effluvium

Lupus

Secondary syphilis

Congenital atrichia

Page 38: Alopecia areata and recent advances

PROGNOSIS

• The extent of AA involvement is probably the most important

prognostic factor.

• Alopecia areata does not destroy hair follicles & the potential

for regrowth of hair is retained for many years and is possibly

lifelong.

• The course of AA is unpredictable. Up to 50% of patients will

recover within 1 year even without treatment.

• In AT/AU, the chance of full recovery is less than 10%.

Page 39: Alopecia areata and recent advances

Other factors associated with a poor prognosis include -

A long duration of hair loss

Atopy

A positive family history

Loss of eyebrows and eyelashes

Recurrent episodes

The presence of other autoimmune diseases

Nail involvement

Young age at first onset

Associated genetic disorders (Down syndrome)

Patchy regrowth of terminal hairs within patch

MIF 173*C gene

Page 40: Alopecia areata and recent advances

INVESTIGATIONS

1. Hair Pull test

2. Hair Pluck test

3. Scalp Biopsy

4. Trichoscopy

5. SALT score ( severity of alopecia tool score)

6. Optical Coherence Tomography- detect hair shaft

abnormalities.

Page 41: Alopecia areata and recent advances

41

Hair Pull Test(Sabouraud’s Sign)

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42

• Telogen hair is easily extracted than anagen hair

• PROCEDURE-

1. About 60 hairs- pulled with constant traction

2. Bulb of extracted hair is examined

3. The number of telogen hair is counted

4. Expressed as percentage of total hair pulled.

• >10 % hairs/area - effluvium

• Telogen effluvium, anagen effluvium, loose anagen syndrome,

early cases of patterned alopecia & the advancing edge of

alopecia areata

Page 43: Alopecia areata and recent advances

43

Drawbacks of this test:

• Washing hair before - may give false low no. of telogen hair.

• Frequency of telogen shedding varies day to day.

• Seasonal variation – inc. spring & autumn.

• More in the frontal & vertex region compared to occipital region.

• Alopecia - failure of development of new anagen hair rather than increased telogen hair ratio. In these patients hair pull test is normal.

Page 44: Alopecia areata and recent advances

44

Trichogram (Hair Pluck Test)

Page 45: Alopecia areata and recent advances

45

The plucked hairs are arranged side by side on a glass slide and taped

Page 46: Alopecia areata and recent advances

46

Anagen hair - forcibly plucked

terminal anagen hair showing

the pigmented bulb with

'hockey-stick' appearance.

Page 47: Alopecia areata and recent advances

47

Telogen hair - forcibly plucked

early telogen hair showing the

Hypo pigmented, club-shaped

cornified bulb with remanents of

the cornified epithelial sac.

Page 48: Alopecia areata and recent advances

SALT ScoreScalp is divided into 4 areas namely :

1. Vertex - 40% of scalp surface area;

2. Right profile of scalp - 18% of scalp surface area;

3. Left profile of scalp - 18% of scalp surface area;

4. Posterior aspect of scalp - 24% of scalp surface area.

• Percentage of hair loss in any of these areas is percentage

hair loss multiplied by percent surface area of the scalp in

that area.

• SALT score is the sum of percentage of hair loss in all above

mentioned areas.

Page 49: Alopecia areata and recent advances
Page 50: Alopecia areata and recent advances

For e.g. - If the percentage hair loss in vertex, right

profile, left profile and posterior aspect is 20, 30, 40

and 50% respecively; then

SALT score = (20 × 0.4) + (30 × 0.18) + (40 × 0.18) +

(50 × 0.24)

= 8 + 5.4 + 7.2 + 12 = 32.6

Page 51: Alopecia areata and recent advances

SALT IIAn updated SALT II score include smaller increments of scalp

coverage to facilitate the assessment of hair loss:

(a) where small patches of hair loss predominate, such as in AA or

cicatricial alopecia

(b) where only certain areas of the scalp are involved, such as in

male pattern hair loss and frontal fibrosing alopecia (FFA).

• 1% of the SSA was approximately 7 cm .

• Efficacy assessments can be done by noting the density in each

of the areas of the involved scalp.

2

Page 52: Alopecia areata and recent advances
Page 53: Alopecia areata and recent advances

Histopathology

• Anagen follicles - Perifollicular and intrafollicular inflammatory

cell infiltrate, concentrated in and around the

hair bulb.

• Inflammatory infiltrate - Activated T lymphocytes, mainly CD4

cells, and macrophages, Langerhans cells and NK cells.

• No inflammatory infiltrate is seen around the isthmus of the

hair follicle, the site of hair follicle stem cells.

Page 54: Alopecia areata and recent advances

• Normal numbers of follicles are found in bald patches and in

alopecia universalis.

• Both anagen and telogen follicles present, with a higher

proportion of telogen follicles.

• Follicles are smaller than normal and anagen follicles do not

develop beyond the anagen III–IV stage.

• The inflammatory infiltrate tends to be less pronounced in AU

than in early lesions and is associated mainly with anagen

follicles.

Page 55: Alopecia areata and recent advances

• Acute stage - Peribulbar lymphocytic infiltrate ‘‘swarm of bees’’

preferentially targets anagen stage follicles.

• The infiltrate is composed of both CD4 and CD8 cells with the

CD4/CD8 ratio being higher in clinically active disease.

• Edema, microvesiculation, apoptosis, necrosis, macrophages, and

foreign body giant cells can be seen in and around the affected hair

follicles.

• Trichomalacia with marked narrowing of hair shafts ‘‘pencil point

hair’’ results in fragile hairs that fall from the scalp in great nos.

Page 56: Alopecia areata and recent advances

Fig. Classic peribulbar ‘‘swarm of bees’’ inflammation in alopecia areata.

Page 57: Alopecia areata and recent advances

Fig. Abnormal hair shaft formation(trichomalacia), a sign of active alopecia areata.

Page 58: Alopecia areata and recent advances

• Subacute stage - large numbers of catagen hairs, followed by

telogen hairs are observed.

• The percentage of catagen/telogen is markedly increased.

• Some remnant inflammation may persist in or around fibrous

tracts as the follicles ascend to telogen level.

Catagen transformation in subacute alopecia areata

Page 59: Alopecia areata and recent advances

Chronic stage - Marked hair follicle miniaturization.

• Terminal to vellus scalp hair follicle ratio is reduced & is likely to

be 1:1.

• These miniaturized anagen follicles are situated slightly deeper

than normal vellus follicles.

• Chronic lesions - presence of nanogen follicles (an intermediate

stage between terminal and vellus anagen).

• Nonsclerotic fibrous tracts extend into the subcutis.

• The inflammatory infiltrate is likely to be in the papillary dermis

around miniaturized follicles.

Page 60: Alopecia areata and recent advances

Fig. Nanogen follicle (intermediate stage, between terminal and vellus anagen) is very typical of alopecia areata.

Fig. Marked miniaturization: a feature of long-standing alopecia areata.

Page 61: Alopecia areata and recent advances

Management

General principles

• Many treatments can induce hair growth in alopecia areata,

but none has been shown to alter the course of the disease.

• The response rate in patients with extensive hair loss is low.

• Counselling is of paramount importance.

• Leaving alopecia areata untreated is a legitimate option for

many patients.

Page 62: Alopecia areata and recent advances

Fig. Treatment algorithm for alopecia areata involving the scalp. DPCP, Diphenylcyclopropenone; ILCS, intralesional corticosteroids; PRN, as needed; SADBE, squaric acid dibutylester.

Page 63: Alopecia areata and recent advances

TOPICAL THERAPY

INTRALESIONAL CORTICOSTEROIDS

• For adult patients with less than 50% scalp involvement, ILCSs,

preferably triamcinolone acetonide are considered first-line

therapy.

• Concentrations - 2.5 to 10 mg/mL (preferred - 5mg/mL)

• Treatment should be stopped if no improvement after 6 months.

• Porter and Burton showed that hair regrowth was possible in

64% of AA sites treated by intralesional injections of

triamcinolone acetonide.

Page 64: Alopecia areata and recent advances

• For the eyebrows and face - 2.5 mg/mL can be used (0.5 mL

to each eyebrow).

• Every 4 to 6 weeks, triamcinolone acetonide is injected

intradermally with a long 30-gauge needle as multiple 0.1 mL

injections at 1 cm intervals.

• Side effects - Transient atrophy and telangectasia, which can

be prevented by :

1. Use of smaller volumes,

2. Minimizing the number of injections per site,

3. Avoiding too superficial (intraepidermal) injections.

Page 65: Alopecia areata and recent advances

TOPICAL CORTICOSTEROIDS

• Topical midpotent corticosteroids are the treatment of choice in

children.

• In limited patchy alopecia, a potent topical steroid delivered in

lotion, foam etc. may hasten the recovery of hair growth.

• Some authors combine topical corticosteroids with minoxidil 5%.

• Tosti et al showed in a study of topical application of 0.05%

clobetasol in alopecia totalis & universalis patients that :

Almost complete hair regrowth - 28.5% of patients,

Long-term benefit - 17.8% of patients.

Page 66: Alopecia areata and recent advances

• Different forms of topical corticosteroids have been used to

treat AA, with varying degrees of efficacy.

• Relapse rate - 37% to 63%.

• Treatment should be continued for at least 3 months.

• Folliculitis is an occasional complication.

• For mild to moderate AA, a prospective, randomized controlled,

double blind trial showed a more than 75% hair regrowth rate

in 61% of patients using 0.1% betamethasone valerate foam.

Page 67: Alopecia areata and recent advances

Minoxidil

• Minoxidil 5% is mainly used as adjuvant treatment to

conventional therapy.

• Minoxidil (2, 4-diamino-6-piperidinopyrimidine-3-oxide) was

initially developed as an antihypertensive therapy. Its mode of

action is not fully understood.

• Mechanisms of action - vasodilatation, angiogenesis, enhanced

cell proliferation, and potassium channel opening.

• There are some reports indicating that minoxidil also has some

immunosuppressive effects.

Page 68: Alopecia areata and recent advances

• Topical minoxidil is far less effective in AT and AU.

• Contact dermatitis - 6% of patients using 5% minoxidil sol.

• Incidence of pruritus much reduced with Minoxidil 5% foam

as compared to the 5% minoxidil solution (1.1% vs 6%).

• Hypertrichosis (facial hair growth) - 3% of patients.

• A double-blind, placebo-controlled trial of 3% topical minoxidil

in extensive AA by Price et al showed hair regrowth in 63.6%

and 35.7% in the treated and placebo groups, respectively.

Page 69: Alopecia areata and recent advances

Anthralin

• Anthralin 0.5% to 1% short contact therapy is used as

alternative treatment.

• Mild irritation should develop in order for it to work.

• Anthralin should not be combined with corticosteroids.

• Treatment may be stopped if no improvement after 3 months.

• Mechanism of action - Unknown, but in mouse studies, it has

been shown to decrease the expression of TNF-α and TNF-β in

the treated area in comparison to vehicle-treated sites.

Page 70: Alopecia areata and recent advances

• Schmoeckel et al showed response rates of 75% in

patchy AA patients and 25% in AT patients.

• Adverse effects to anthralin include -

1. Severe irritation

2. Folliculitis

3. Regional lymphadenopathy

4. Staining of skin, clothes, and fair hair.

• Patients should avoid eye contact with this chemical.

Page 71: Alopecia areata and recent advances

TOPICAL IMMUNOTHERAPY

• Diphenylcyclopropenone (DPCP) is the treatment of choice for

adults with ˃ 50% scalp involvement.

• Squaric acid dibutylester is an alternative in patients who do

not develop allergic reaction to DPCP.

• Treatment to be stopped if no improvement after 6 months.

• Success rate - 50% to 60%

• Relapse rate - up to 62% at a median period of 2 & a half yrs.

Page 72: Alopecia areata and recent advances

Contact sensitizers that have been used in the treatment of AA

include -

1. Dinitrochlorobenzene (DNCB),

2. Squaric acid dibutylester (SADBE), and

3. Diphenylcyclopropenone (DPCP).

• DPCP is the topical sensitizer of choice because SADBE is not

stable in acetone.

• Negative prognostic factors in the treatment of AA with DPCP –

1. Disease severity

2. Duration of AA before therapy

3. Presence of nail changes.

Page 73: Alopecia areata and recent advances

Mechanism of action of topical sensitizers:

1. Antigenic competition with CD4 cells.

2. Perifollicular lymphocytes apoptosis.

3. Changes in the peribulbar CD4/CD8 lymphocyte ratio.

4. Regularization of HLA expression in hair follicle.

• New non specific suppressor T lymphocytes compete with local

lymphocytes which are activated against follicular antigen.

• Hoffman et al hypothesized that IL-10 secretion from basal

keratinocytes or lesional T cells after DPCP application results in

an inhibitory effect on lesional T cells.

Page 74: Alopecia areata and recent advances

• Initially, 2% DPCP in acetone is applied to a 4 × 4cm circular area

of the scalp to sensitize the patient.

• Two weeks later, a 0.001% DPCP solution is applied to the same

half of the scalp. The concentration of DPCP is sed gradually

each week until a mild dermatitis reaction is obtained.

• The goal is to achieve a low-grade erythema and mild pruritus on

the treated area for 24 to 36 hours after application.

• A mild eczematous reaction is intrinsic to therapy.

Page 75: Alopecia areata and recent advances

Adverse effects include –

1. Vesicular or bullous reaction

2. Cervical and occipital lymphadenopathy

3. Facial and scalp edema

4. Contact urticaria

5. Flu-like symptoms

6. Erythema multiforme like reactions

7. Pigmentary disturbances.

• Although DPCP has not been shown to be teratogenic, as a

precaution, pregnant women should not use it.

Page 76: Alopecia areata and recent advances

SYSTEMIC THERAPY

Systemic corticosteroids

• Daily, weekly, and monthly pulse corticosteroids have been used

with varying success.

• Limited use because of side effects and higher rate of relapse.

• Better success rates in multifocal AA and less favorable results

with ophiasis and universalis AA.

• In a placebo-controlled trial of oral prednisolone 200 mg once

weekly for 3 months, it was shown that a moderate regrowth

of hair (31-60%) was possible in 30% of prednisolone patients.

Page 77: Alopecia areata and recent advances

MECHANISM OF ACTION OF GLUCOCORTICOIDS

• CS-GCR complexes prevent the binding to their target genes of

a variety of natural transcription factors (such as AP1, NF AT ‐and NF κB), resulting in the reduced expression of many ‐immunoregulatory and pro inflammatory proteins.‐

• Non genomically mediated actions of GC :‐ Release of the protein chaperones - signalling effects.

Via this mechanism, GCs impair TCR signalling and

consequently, T cell cytokine production, proliferation and ‐ differentiation.

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• The addition of 2% topical minoxidil three times daily may

alleviate post-steroid relapse.

• Corticosteroid pulse therapy seems to have less of a side effect

profile than daily or alternate day oral regimens.

• Dosages vary from initial 20–40 mg prednisone daily tapered

down to 5 mg daily in a few weeks.

or

• Different pulse therapies regimens with short-term high doses of

oral prednisolone (100–300 mg) or i.v. methylprednisolone(250

mg).

Page 79: Alopecia areata and recent advances

• A study by Sharma et al of twice weekly 5-mg dexamethasone

minipulse therapy for the treatment of extensive AA showed:

Complete to excellent (75% 95%) hair growth in 53.3% of ∼patients.

• A study by Jang et al also found an effective response to

betamethasone minipulse therapy, with vellus and/or terminal

hair growth for more than 1 month occurring in 67.4% of

patients.

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In a first systematic review on the use of PCT for AA :

• Complete response - 43% of the total study population

51% of the pediatric-only studies.

• Relapse rate - 17% for the total study population

60% for the pediatric-only population.

• Side effects were reported in 21% of the study population.

• Patients who responded to treatment had low relapse rates,

suggesting that in patients with good prognostic factors, PCT

may be beneficial.

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Photochemotherapy

• Systemic and topical psoralen plus ultraviolet A light

phototherapy have been used with limited success.

• Long-term safety, side effects, and a high relapse rate have

curtailed the use of PUVA therapy.

• The response rates for oral or topical PUVA phototherapy ranges

from 15% to 70% in uncontrolled trials.

• Two large retrospective studies showed that the response rate is

no better than the spontaneous remission rate.

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Cyclosporine

• Cyclosporine has been used alone or in conjunction with

corticosteroids with a success rate up to 76.6%.

• Cyclosporine is an immunosuppressant agent that inhibits

helper T-cell activation and suppresses IFN-γ production.

• Notably, however, AA has been reported in several organ

transplant patients who were taking cyclosporine.

• Its use is not generally recommended because of its adverse

effect profile, high relapse rate, and the long-term treatment.

Page 83: Alopecia areata and recent advances

• In a comparative study by Jang et al, the response rates of:

Cyclosporine group - 54.9%

Betamethasone minipulse group - 37.8%.

• In the cyclosporine group, patients with mild AA were found to

respond better to the treatment.

• 70.6% of patients in the cyclosporine group and 43.2% of

patients in the BMP group rated their hair regrowth as excellent

or good.

• Oral cyclosporine appeared to be superior to BMP therapy in

terms of treatment effectiveness and safety.

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Tacrolimus

• Initial trials revealed a potential for alopecia areata.

• Peculiarity was that induction of anagen and hair growth

promotion was more with topical preparation than systemic

tacrolimus administration.

• Yamamoto et al reported in their findings that tacrolimus

stimulated hair growth in mice.

• A study by Price et al in 11 patients with mild to moderate

alopecia areata had no terminal hair growth in response to

tacrolimus ointment 0.1% applied twice daily for 24 weeks.

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Methotrexate• In a retrospective uncontrolled trial of weekly 20 to 25mg

methotrexate combined with 20 mg/d oral prednisone in 22

AT/AU patients, total recovery occurred in 14 patients (64%).

• These results need to be confirmed in randomized controlled

studies.

Biologics• Several reports of multiple biologics, including etanercept,

efalizumab, adalimumab, and infliximab failed to show

improvement in AA.

Page 86: Alopecia areata and recent advances

Sulfasalazine

• Sulfasalazine up to 1.5 g twice daily is successful in

about a quarter of the patients.

• The relapse rate is 45.5%

• One in three patients may have side effects which

included GI distress, rash, headache, and laboratory

abnormalities.

Page 87: Alopecia areata and recent advances

RECENT ADVANCES IN TREATMENT

OF ALOPECIA AREATA

Page 88: Alopecia areata and recent advances

Bexarotene

• In a single recently published study, bexarotene 1%

gel resulted in a 26% hair regrowth rate.

• Dermal irritation is a common side effect.

• The mechanism of action is thought to be through

immunomodulation and induction of T-cell

apoptosis.

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Capsaicin

• Capsaicin was previously shown to induce vellus hair regrowth in

alopecia areata.

• More recently, a study showed that topical capsaicin and

clobetasol 0.05% are comparable.

• Idea of using capsaicin in AA emerged from the theory of nervous

system & neuropeptide role in the development of the disease.

• Capsaicin can release substance P (SP) and calcitonin gene related

peptide (CGRP), & after repeated application, it depletes neurons

of SP.

Page 90: Alopecia areata and recent advances

HYDROXYCHOLOROQUINE

• Hydroxychloroquine, an antimalarial, is considered an

important cutaneous immune modulator.

• Antimalarials possess a lysosomotropic action interfering with

normal physiologic action of subcellular compartments,

leading to a decreased production of cytokines and other

inflammatory mediators.

• Dr. stephan et al reported 2 cases of AT that were not

responding to other modalities of treatment & showed an

excellent response to hydroxychloroquine.

Page 91: Alopecia areata and recent advances

Before starting HCQ therapy (left) and regrowth of hair after 2 months of HCQ therapy (right).

Page 92: Alopecia areata and recent advances

AZATHIOPRINE

• A study by Farshi et al showed that treatment with

azathioprine

as a systemic monotherapy clinically produces relevant

improvement in moderate-to-severe alopecia areata.

• Generally azathioprine is a low-cost and well-tolerated drug

and with controlled studies on larger number of patients,

long-term efficacy and safety of this treatment should be

investigated.

Page 93: Alopecia areata and recent advances

Oral zinc sulphate

• In a study by Fattah et al, a significantly lower serum zinc level

was found in patients with AA compared to controls and was

significantly lower in patients with resistant AA compared to

patients with newly diagnosed AA.

• In a study by Park et al on 15 patients, hair regrowth was

observed in 9 patients (67%) in response to oral zinc

supplementation.

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STEM CELL THERAPY

• A study by Yanjia et al demonstrated that patients with severe

AA achieved improved hair regrowth and quality of life after

receiving Stem Cell Educator therapy.

• Flow cytometry revealed the up-regulation of Th2 cytokines

and restoration of balancing Th1/Th2/Th3 cytokine production.

• IHC indicated the formation of a “ring of TGF-β1” around the

hair follicles, leading to restoration of HF IP & the protection of

newly generated hair follicles against autoimmune destruction.

Page 95: Alopecia areata and recent advances

PRP IN ALOPECIA AREATA

• Platelet-rich plasma is defined as autologous blood with a

concentration of platelets 4-7 times above baseline values.

• PRP is known to contain more than 20 different growth factors.

• In a study by Kumar et al, administration of autologous PRP has

led to observable hair regrowth in 70% of patients with mean

decrease in SALT Score.

• A study by Katsuoka et al has shown in vitro that PRP stimulates

the proliferative phase and transdifferentiation of hair stem cells

and hereby produce new follicular units.

Page 96: Alopecia areata and recent advances

Recombinant Human Bone Morphogenetic Protein

• It is involved in hair morphogenesis.

• In a case report by Leslie et al, a patient of alopecia universalis

who used it for bone fracture healing responded with dramatic

hair growth all over body.

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Fractional Photothermolysis Laser

• A single case report of a 35-year-old male patient who had AA

for 2 years and who was nonresponsive to treatment with

minoxidil, topical corticosteroids, and ILCSs had complete

regrowth after multiple sessions with fractional Er:Glass laser.

• Hair growth was noted as early as 1 month, and complete re

growth was achieved at 6 months. No hair loss was reported in

the 6-month follow-up period. No side effects were reported.

• The mechanism of action is thought to involve the induction of

T-cell apoptosis and direct enhancement of hair growth.

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Prostaglandin analogues

• Latanoprost, a PGF 2α analogue, and bimatoprost, a synthetic

analogue showed stimulatory effects on murine hair follicles

and follicular melanocytes in telogen & anagen phases and

enhanced the conversion from the telogen to the anagen stage.

• In December 2008, bimatoprost ophthalmic solution (Lattisse)

received approval from the US FDA for the treatment of

hypotrichosis of the eyelashes.

• Treatment is well tolerated apart from mild erythema and

itching in a few patients.

Page 99: Alopecia areata and recent advances

TOPICAL CALCIPOTRIOL

• 1, 25-dihydroxycholecalciferol is the biologic active form of the

vitamin D3. Vit. D has a multitude of biologic effects interacting

with the innate and adaptive immune system.

• It regulates the differentiation of B cells, T cells, dendritic cells,

and the expression of Toll-like receptors.

• There is growing evidence that vitamin D may help in several

autoimmune diseases like type I DM, lupus, and rheumatoid

arthritis etc.

Page 100: Alopecia areata and recent advances

• In a case report by King et al from Korea of a 7-year-old boy

with reduced VDR expression in AA showed that –

• Initial new hair growth was found at 6 weeks after initial

application of calcipotriol.

• After 3 months of calcipotriol therapy, complete regrowth was

observed in the affected area.

• On IHC staining , VDR was detected in some nuclei of the

keratinocytes in the hair follicles in previously affected area.

• No hair loss relapse was observed over the next 6 months.

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Immunomodulators from parasites

• Human namatode infection results in decreased production of the

cytokine IFN-γ, but increased production of the cytokines IL-4 and

IL-10 and the antibody type Ig G4, TH2 cell response.

• This shift may change the susceptibility to TH1-associated

immune responses, such as cell-mediated autoimmune diseases.

• The production of harmless nematode antigen that is able to elicit

such a response may have some value in treating autoimmune

diseases, including AA.

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RUXOLITINIB

• A JAK1/2 inhibitor currently FDA approved for the treatment of

myeloproliferative disorders.

• An open-label clinical trial of 12 patients with moderate-to-severe

AA was conducted using oral ruxolitinib, 20 mg twice per day, for

3–6 months of treatment followed by 3 months follow-up off drug.

• 75% patients demonstrated a remarkable response to treatment,

with average hair regrowth of 92% at the end of treatment. Safety

parameters remained largely within normal limits, and no serious

adverse effects were reported.

Page 103: Alopecia areata and recent advances

• Even the most severe forms of alopecia, AT/AU, responded,

indicating that the autoimmune process remains pathogenically

active and remains reversible with JAK inhibition.

• Gene expression profiling revealed treatment-related

downregulation of inflammatory markers, including signatures for

CTLs and IFN response genes and upregulation of hair-specific

markers.

• Larger randomized controlled trials are needed to further assess

the safety and efficacy of ruxolitinib in the treatment of AA.

Page 104: Alopecia areata and recent advances

TOFACITINIB CITRATE• It is a pan-JAK inhibitor.

• A 2-centre, open-label, single-arm trial for AA with >50% scalp

hair loss, alopecia totalis (AT) and alopecia universalis (AU).

Tofacitinib (5 mg) was given twice daily for 3 months.

• Of 66 subjects treated, 32% experienced 50% or greater

improvement in SALT score. Diffuse AA and ophiasis subtypes

were more responsive than AT and AU subtypes.

• Drug cessation resulted in disease relapse in 8.5 weeks.

• Adverse events were limited to grade I and II infections.

Page 105: Alopecia areata and recent advances

BARICITINIB

• A patient with AA was enrolled in a clinical trial to examine the

efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant

CANDLE syndrome. The patient exhibited a striking

improvement of his AA on baricitinib over several months.

• In vivo, studies using the C3H/HeJ mouse model demonstrated

a strong correlation between resolution of the interferon

profile and clinical improvement during baricitinib treatment.

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USTEKINUMAB

• Ustekinumab is a fully human monoclonal antibody to the

shared p40 subunit of IL-12 and IL-23.

• IL-12 is the key effector cytokine in commitment to a TH1

response.

• IL-23 is a newly discovered cytokine that is thought to play an

important role in linking the innate and adaptive arms of the

immune response.

• Ustekinumab was proven to be efficacious in plaque psoriasis.

It may be tried on AA patients in the future.

Page 107: Alopecia areata and recent advances

THANK YOU