This document provides an overview of recent advances in the treatment of alopecia areata. It discusses the pathophysiology of the condition and classifications based on extent and pattern of hair loss. Emerging therapies that target the JAK-STAT signaling pathway like baricitinib, ritlecitinib, and deuruxolitinib are showing promising results in clinical trials. Other treatments discussed include dupilumab, ustekinumab, abatacept, and platelet-rich plasma therapies. Future areas of research mentioned are studying the role of the microbiome and fecal transplants in alopecia areata.

1. Recent Advances in Alopecia
Areata
MODERATOR: Dr Surendra Kumar Thalor sir
PRESENTER: Dr Pawan Kumar

2. INTRODUCTION
• First described by Celsus (25 BC)
• Term was coined by Sauvages in 1763
• AA is a common, chronic, inflammatory disease that causes
non‐scarring hair loss.
• The severity ranges from small patches of hair loss, which usually
recover spontaneously, to complete alopecia where the prognosis for
hair regrowth is poor.

3. • Caused by a T‐cell‐mediated autoimmune mechanism occurring in
genetically predisposed individuals.
• Environmental factors may be responsible for triggering the disease.
• Associated with other autoimmune diseases
• Atopic disease
• Thyroiditis
• Lupus erythematous
• Vitiligo
• Psoriasis

4. Pathophysiology
• Hair follicle considered as a immune privileged site bcz low or
absent expression of MHC 1 proteins.
• Reduced risk of attracting autoimmune CD8+ T cells.
• In healthy hair follicle epithelium, down regulation of MHC class I
and ligands of NK cells receptors by increase in alpha MSH , TGF b &
IGF 1.
• Loss of immune privilege of the hair follicle have major role in AA .

5. • In genetically predisposed individuals , INF gamma upregulate
• MHC proteins
• NK cell ligands like MICA & ULBP3
• Leads to collapse of immune privilege & attack by CD8+ T cells.
• Cytotoxic CD8+ NKG2D+ T cells are main pathogenic cells.
• These CD8+ T cells secrete INF gamma. -> IL – 15 & IL – 15 R by
follicular keratinocytes -> promotes and sustains T cell
autoreactivity.

6. • IL-15 binds to the CD8 + T cells, further stimulating production
of IFN-γ via JAK1 and JAK3 signaling.
• Human AA lesion biopsies have shown overexpression of the
signaling of IFN-γ, JAK3, and, to a lesser degree,JAK1 and JAK2.
• There is inflammatory infiltrate around hair bulb.
• Anagen follicles are prematurely precipitated in telogen phase.
• Anagen follicles don’t progress beyond stage 3-4

8. CLASSIFICATION OF AA
• Based on extent
• Patchy alopecia
• Alopecia totalis
• Alopecia universalis
• Based on pattern
• Reticular
• Ophiasis
• Sisaipho
• New variants
• Acute and diffuse total alopecia
• Unusual patterns
• Perinevoid alopecia
• Linear

9. Ikeda classification of AA
Based on associated conditions and course of disease.
1. Atopic type: It begins early in life and mostly (30-75%) progresses to
Alopecia totalis
2. Autoimmune type: It is seen in middle-aged groups associated with
autoimmune diseases, diabetes mellitus and progresses to AT in 10-
50%.
3. Prehypertensive type: It is seen in young adults whose parents were
hypertensive and progress fastly to AT in 40% of cases.
4. Common type: It affects adults aged 20-40 years and AT develops in 5-
15% of cases

11. EMERGING THERAPIES
1. Janus kinase (JAK) Inhibitors
• Baricitinib JAK1, JAK2 inhibitors
• Ritlecitinib JAK 3 inhibitor
• Deuruxolitinib (CTP-543) JAK1, JAK2 inhibitor
• Tofacitinib JAK1, JAK3 inhibitors
• Ruxolitinib JAK1, JAK2 inhibitors
2. Dupilumab
3. Ustekinumab
4. Abatacept
5. Platelet Rich Plasma Therapies

12. JAK Kinase Inhibitor
• JAK inhibitors work on the JAK-STAT pathway which plays a significant
role in the maintenance of innate and adaptive immunity
• Available as Oral and topicaldrugs
• Selective but not specific for a single JAK and thus can affect various
immunologic pathways
• It works as downstream effectors of the IFN-γ and γ c cytokine receptors

13. • Interferes with the positive feedback loop between the follicular
cell and the cytotoxic CD8 + NKG2D + T cells in AA
• Stimulates hair follicle stem cells and an antiquiescence signal
during the telogen phase, accelerating re-entry into the anagen
phase.
• Also prevent the production of inflammatory Th17 cells and Th1
and Th2 differentiation

16. • Baricitinib :
• Selectively inhibits JAK1 and JAK2 and, to a lesser extent TYK2.
• U.S. FDA approved baricitinib oral tablets to treat adult
patients with severe alopecia areata in 2022 & for rheumatoid
arthritis in 2018.
• In two double blinded clinical trials, BRAVE-AA1 & BRAVE-AA2,
total 1200 patients with severe AA(SALT >50) were included in
phase 3 studies
• 19.7% (67/340) Patients receiving 2 mg baricitinib orally for 36 weeks
have >20 SALT improvement.
• 34% (175/515) Patients receiving 4 mg baricitinib orally for 36 weeks
have >20 SALT improvement.

17. • Adverse effects following baricitinib mostly seen after 4mg dosing
which are
• URTI (21.3%)
• Headache (6.6%)
• Acne (5.9%)
• Hyperlipidemia (5.9%)
• Serious adverse events – arterial thrombosis , B - cell lymphoma
observed in <1% patients.

18. Ritlecitinib
• Ritlecitinib is a selective inhibitor of JAK3.
• In a quadruple blinded RCT of 718 patients (SALT>50) received 30mg or
50mg oral ritlecitinib for 24 weeks.
• 30.6% (38/124) of patients receiving 50mg showed >20% improvement in SALT score
• 22.3% (27/121) of patients receiving 30 mg showed >20% improvement in SALT score
• Common reported S/E -
• Nasopharyngitis (14%)
• URTI (12%)
• Headache (12.8 %)
• Acne, diarrhoea & nausea

19. Deuruxolitinib (CTP – 453)
• Orally administered compound modified from ruxolitinib
• Selective inhibitor of JAK 1 & 2.
• Double blinded RCT (King et al) of 145 patients(SALT >50) showed
achievement in SALT <20% in dose dependent manner at 24 weeks
• 41.7% (15/36) patients achieved SALT <20 with 12mg /day oral deuruxolitinib.
• 26.3% (10/38) patients achieved SALT <20 with 8mg /day.
• 14.3% (4/28) patients achieved SALT <20 with 4 mg /day.
• Common adverse events occurrence in 12mg/day dosing
• acne (16.7%)
• headache (19.4%),
• nasopharyngitis (25.0%)
• upper respiratory tract infection (19.4%)
• No dose dependent change in adverse effects.

20. Ruxolitinib
• Selective inhibitor of JAK 1 & JAK 2
• Available in cream and tablet form
• US FDA approved for treatment of myelofibrosis
• In a double blind clinical trial (Olsen et al) of 78 AA patients showed
no statically significant benefit from ruxolitinib cream twice local
application compared to placebo.

21. • In open label comparative study(Almutairi et al) of 38 AA patients
(SALT >30) given 20 mg ruxolitinib orally twice daily for 6 months
• 84% (32/38) achieved SALT 50
• 73% patients has relapse after 3 months of stopping the drug
• adverse effects – leukopenia , elevated liver enzymes, infections,
headaches, fatigue, abdominal pain , diarrhoea , weight gain.

22. Tofacitinib
• Selectively inhibits JAK1- and JAK3, with minimal effects on TYK2
• US FDA approved for Rheumatoid arthritis in 2012.
• In open label comparative study (Almutairi et al) of 37 AA
patients(SALT>30) received tofacitinib 5mg tab. twice daily
for 6 months.
• 78.4% (29/37) achieved SALT 50 at end of 6 months
• After 3 months of stoppage of drug 70% patients have relapse.
• Adverse effects – leukopenia , elevated liver enzymes,
triglycerides elevation, tonsillitis, UTI, folliculitis, genital
warts, headache & weight gain.

23. Dupilumab
• Monoclonal antibody directed against the IL-4 receptor α (IL-4Rα) subunit
blocking both IL-4 and IL-13 signaling pathways.
• US FDA approved for the treatment of atopic dermatitis (AD)
• In AA:
• By binding with IL-4α subunit – inhibits downstream JAK- STAT pathway
• inhibition of Th2 pathway activation found in AA scalp lesions.
• Double blind RCT (Emma Guttman et al) with 60 patients with >30% hair
loss received either sc injections of dupilumab 300mg/week or placebo for
24 weeks
• 10% (4/40) of patients achieved SALT 50 compared to none in placebo.
• Mc adverse effects: URTI, conjunctivitis, injection site reactions,
gastrointestinal symptoms, eosinophilic dermatitis & fatigue.

24. Apremilast
• PDE 4 inhibitor
• US FDA approved for psoriatic arthritis
• In AA : Prevents hydrolysis & inactivation of cAMP, which dampens
pro- inflammatory immune response of IL – 12,17A,22&23.
• Double blind RCT(Mikhaylov et al) on 20 patients with AA(>50% scalp
involvement) received 30mg oral aprmilast or placebo twice daily for
24 weeks
• No significant improvement seen in treatment group ( 1patient achieved
SALT50 in both groups)
• Adverse effects – nausea, diarrhoea & no serious side effects
observed.

25. Ustekinumab
• Is an IL-12/IL-23 monoclonal antibody currently used as an effective
treatment for psoriasis and Crohn’s disease.
• Genetic expression of immune and keratin markers with higher
inflammatory profile and greater suppression of hair keratins at baseline
were associated with higher recovery of hair regrowth.
• Common adverse effects include injection-site reactions,headache, and
fatigue.
• Shown to cause hair regrowth in three patients with moderate to severe
AA in a case series by Emma Guttman et al.

26. Abatacept
• Currently approved for the treatment of RA and juvenile idiopathic
arthritis.
• Abatacept is a CTLA4–immunoglobulin costimulatory modulator that
attenuates the activation of T cells.
• Common adverse effects are headache, dizziness,nasopharyngitis,
cough, back pain, and hypertension.
• open-label, single-arm clinical trial (Julian Mackay et al) of abatacept
(125 mg subcutaneously daily for 24 weeks) in 15 patients
• 5 subjects showed intermediate hair growth

27. Platelet-Rich Plasma Therapies
• It involves an autologous blood product of centrifuged whole blood
with subsequent extraction of various proportions of the plasma and
platelets or buffy coat.
• PRP is rich in platelets and growth factors (GFs), such as platelet-
derived GF, fibroblastic GF, epithelial GF, insulin-like GF, TGF, and
VEGF.
• These GFs can contribute to wound healing via stimulation of
fibroblasts, neocollagenesis, neoangiogenesis, and recruitment of
mesenchymal stem cells, which then differentiate at the site of injury.

28. • When the alopecia area is injected locally,PRP can affect hair
growth via induction and maintenance of the anagen phase of
the growth cycle
• PRP injections may have limited benefit in patients with
chronic and severe cases of AA with increase hair regrowth
and decreased hair dystrophy

29. Future Treatment Directions
• Recent advances in the understanding of the microbiome and its role in
autoimmunity is a popular area of study
• Microbiome dysbiosis has been noted in patients with AA
• Two patients with AA experienced hair regrowth after receiving fecal
transplant for the treatment of Clostridium difficile (Rebello D. et al 2017)
• Adverse effects associated with fecal transplants include transmission of
multi-resistant organisms, vomiting,fever, diarrhea, bacteremia, and
peritonitis

33. THANK YOU