alopecia areata and recent advances
TRANSCRIPT
ALOPECIA AREATA AND
RECENT ADVANCES
By : Dr. Ajeet Singh
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.
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.
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
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
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
Multifactorial etiology of alopecia areata
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.
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).
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.
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.
The pathogenesis of alopecia areata
• 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.
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.
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
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.
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.
• 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.
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.
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.
• 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.
• 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.
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.
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.
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.
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.
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.
Patch of alopecia areata showing broken ‘exclamation mark hairs’ towards the margins
Close up of exclamation mark hairs‐
• 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.
Alopecia totalis with a 100% loss of scalp hair
Alopecia universalis
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
• 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.
Sparing of white hairs in a patch of alopecia areata
Regrowth of hypopigmented hair in alopecia areata.
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.
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.
DIFFERENTIAL DIAGNOSIS
Temporal triangular alopecia
Tinea capitis
Trichotillomania
Telogen effluvium
Lupus
Secondary syphilis
Congenital atrichia
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%.
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
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.
41
Hair Pull Test(Sabouraud’s Sign)
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
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.
44
Trichogram (Hair Pluck Test)
45
The plucked hairs are arranged side by side on a glass slide and taped
46
Anagen hair - forcibly plucked
terminal anagen hair showing
the pigmented bulb with
'hockey-stick' appearance.
47
Telogen hair - forcibly plucked
early telogen hair showing the
Hypo pigmented, club-shaped
cornified bulb with remanents of
the cornified epithelial sac.
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.
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
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
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.
• 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.
• 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.
Fig. Classic peribulbar ‘‘swarm of bees’’ inflammation in alopecia areata.
Fig. Abnormal hair shaft formation(trichomalacia), a sign of active alopecia areata.
• 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
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.
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.
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.
Fig. Treatment algorithm for alopecia areata involving the scalp. DPCP, Diphenylcyclopropenone; ILCS, intralesional corticosteroids; PRN, as needed; SADBE, squaric acid dibutylester.
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.
• 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.
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.
• 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.
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.
• 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.
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.
• 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.
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.
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.
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.
• 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.
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.
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.
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.
• 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).
• 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.
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.
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.
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.
• 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.
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.
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.
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.
RECENT ADVANCES IN TREATMENT
OF ALOPECIA AREATA
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.
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.
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.
Before starting HCQ therapy (left) and regrowth of hair after 2 months of HCQ therapy (right).
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.
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.
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.
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.
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.
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.
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.
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.
• 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.
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.
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.
• 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.
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.
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.
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.
THANK YOU