Role of topical calcineurin inhibitors in

pediatric skin diseases

Assist. Prof. Rattanavalai Nitiyarom M.D.,

Department of Pediatrics,
Faculty of Medicine, Siriraj hospital, Mahidol University
 Scope

• Principle of topical therapy

• Topical corticosteroids

• Topical calcineurin inhibitors

 Principle of topical therapy
• Stratum corneum: limit percutaneous absorption of drugs
• Factors affecting percutaneous absorption
– Patient: age, disease, barrier integrity, anatomic location
– Properties of topically applied drug: drug properties, vehicle compositions, application
under occlusion
• Efficacy of a topically applied drug
– Applied drug
– Delivery of the active molecule by its vehicle
• Physicochemical properties of vehicle
– Potency of the active molecule
• Either the vehicle or its active ingredient(s): local - systemic toxicity
Percutaneous absorption

J Invest Dermatol. 1967;48(2):181-83.)

 Formulation and vehicles
Liquid Semisolid Solid
Monophasic solutions Water-free ointments Powders
• Pure aqueous: lotions, gels * Zinc
• Alcohol, alcoholic-aqueous: paints oxide,
• Oily: oils titanium
Emulsions Water-containing dioxide,
• Oil in water (O/W) can be washed off with water • Monophasic: hydrogels talc
• Water in oil (W/O) cannot be washed off with water • Multiphasic: emulsions,
cream (O/W, W/O)
Suspensions Highly concentrated
suspensions
* paste
Aerosols
• Foam
• Spray Bolognia 3rd ed
 Quantity of topical medication usage

1 fingertip unit (FTU) developed by Long and Finlay

5-mm-diameter nozzle
the tip of the palmar aspect of the index finger to
the distal interphalangeal joint skin crease
500 mg = cover about 2% of the BSA/ 2 adult palms
Quantity of topical drug to dispense in adults

Dermatology 4th edition, 2017

Quantity of topical drug to dispense in
children according to age

Dermatology 4th edition, 2017

Topical corticosteroids
 Topical corticosteroids (TCS)

• Mainstay therapy in various skin conditions

• Actions:
– Anti-inflammatory
– Antimitotic
– Immunosuppressive
– Vasoconstrictive---define potency of TCS
Mechanism of glucocorticoid action

Dermatology 4th edition, 2017

 Anti-inflammatory effects of TCS
• Decreased production of cytokines and other proinflammatory
molecules
– Tumor necrosis factor-α
– Granulocyte–macrophage colony-stimulating factor
– Interleukin (IL)-1, IL-2, IL-6 and IL-8
– Intercellular adhesion molecule (ICAM)-1, E-selectin
– Leukotrienes and prostaglandins (due to decreased phospholipase A2
and cyclooxygenase activity)

Dermatology 4th edition, 2017

 Anti-inflammatory effects of TCS:
effects on inflammatory cells
• Neutrophils
– Increased release from the bone marrow,
resulting in neutrophilia due to a larger
circulating pool
– Decreased infiltration into sites of inflammation
due to reduced expression of endothelial
adhesion molecules and chemoattractants
– Decreased apoptosis
– Milder effects on phagocytosis and bactericidal
function
• Eosinophils
– Decreased release from bone marrow and
recruitment to sites of inflammation
– Increased apoptosis
• Monocytes/macrophages
– Decreased production, differentiation, and
antigen presentation
• Lymphocytes
– Redistribution of T cells to lymphoid depots, resulting
in transient lymphopenia
– Decreased activation and proliferation of effector
(helper > cytotoxic) T cells, related to decreased IL-2
signaling and antigen presentation
– Decreased B-cell function and antibody production (at
high doses)
– Increased apoptosis - Increased regulatory T-cell
function
• Mast cells
– Decreased maturation, cytokine production, high-
affinity IgE receptor (FcεRI) expression, and
mediator release
• Erythrocytes
– Decreased destruction due to reduced autohemolysis
and erythrophagocytosis
Dermatology 4th edition, 2017
Topical corticosteroids
WHO potency Class Generic name Tradename
group
Super-potent I Clobetasol propionate 0.05% Clebetate, Dermovate,
(ointment, cream, lotion, shampoo) Clobex
Potent II Desoximetasone 0.25% cream, ointment Topicorte, Topoxy
Esperson
III Betamethasone dipropionate 0.05% cream Diprosone, Betapro
Moderately IV *Mometasone furoate 0.1% cream, lotion Elomet, Momate
potent Triamcinolone acetonide 0.1% cream, ointment TA cream
V Betamethasone valerate 0.1% cream Beta, Betnovate
*Prednicarbate 0.1% cream Dermatop
Low VI Triamcinolone acetonide 0.02% cream TA cream
VII Hydrocortisone 1% cream Hytisone
Prednisolone 0.5% cream Prednisolone cream
 Topical Corticosteroids
• Strength and mode depend on
– Individual disease - Sites to be treated
– Age of the patient - Severity of disease
– Type of skin barrier - Concomitant use of occlusion
– Duration of treatment
– Vehicles:
• Significant effect on the bioavailability of TCS
 Guideline for choosing an appropriate TCS
• Face, skinfolds, and diaper area: low-potency cream or ointment
• Widespread lesions: low to moderate-potency lotion, cream or ointment
• Hair-bearing areas: moderate-potency alcohol-based lotion
• Intraoral lesions: orabase
• Insect bites: ointments with tape occlusion
• Thickened dry lesions:
– Ointments in combination with exfoliant agents
– Intermediate to high potency for the 1st wk
– Decrease potency as improvement occuring
• Secondarily infected lesions:
– Systemic antibiotic therapy
– Wet compresses initiated for 2–5 days before beginning TCS
 Local cutaneous side effects
Atrophy: resolve within 1-4 wks
Striae: do not resolve
Perioral dermatitis
Acne, folliculitis, rosacea
Telangiectasia
Erythema
Hypopigmentation
Hypertrichosis

Dermatology 4th edition, 2017

 To avoid side effects of TCS
• If not abused are very safe
– As needed protocol
• To avoid systemic effects:
– No more than 15 g/mo in infants < 12 mo
– No more than 30 g/mo in children < 10 yrs

J Eur Acad Dermatol Venereol. 2012;26(8):1045–1060.

Topical calcineurin inhibitors
 Topical calcineurin Inhibitors (TCIs)

• Anti-inflammatory agents without side effects of TCS

• Topical macrolide immunomodulators:
– Tacrolimus (Protopic®)
– Pimecrolimus cream (Elidel®)
 Structurally very similar
CI
HO

H3CO H3CO CH3

CH3
H3 C H3 C O
O
H H
O OH O OH CH3
N N
O O
O CH3·H2O O O CH3
O
OH OH
H3 C H3 C
O CH3 O CH3

H3CO OCH3 H3CO OCH3

Tacrolimus Pimecrolimus
 822.05 Da  810.48 Da
 C44H69NO12·H2O  C43H68ClNO11
Tacrolimus
 Tacrolimus
• Produced by Streptomyces tsukubaensis in the Tsukuba region of Japan
• Derived from
– Tsukuba (the mountain the soil sample came from)
– Macrolide (the compound is a hydrophobic macrolide)
– Immunosuppressive
• Introduced as an oral drug preventing transplant rejection in 1989
• Topical form was launched on the market in 2000
• Preparation: 0.03% and 0.1% ointment
• Price: 10 g/tube
– 0.03% ointment: 1,119 baht (112 baht/g)
– 0.1% ointment: 1,258 baht (126 baht/g)
• The anti-inflammatory activity defined as equipotent to moderate-to high-potency TCS
Postepy Dermatol Alergol. 2013 Jun; 30(3): 165–169.
J Dermatol. 2018 Aug; 45(8): 936–942.
Pimecrolimus
• Produced by the fermentation
of Streptomyces hygroscopicus var.
ascomycetous
• Ascomycin derivatives: antifungal
& immunomodulatory compound
• Launched on the market in 2001
• Preparation: 1% cream
• Price: 15 g/tube 912 baht
(61 baht/g)
 Mechanism of actions

• Bind to the FK506-binding protein

(FKBP) form complex
• Become complex of tacrolimus-FKBP-12,
calcium, calmodulin, and calcineurin
• Inhibit phosphatase activity of
calcineurin
• Prevent the dephosphorylation and
translocation of nuclear factor of
activated T-cells (NF-AT)
• Inhibit proinflammatory cytokines
production

Dermatology 4th edition, 2017

 Dermal immune cell targets of TCIs and TCS

T cell Mast cell Basophil Langerhans B cell Macrophage Eosinophils Fibroblast

cell

Pimecrolimus
1,2

Tacrolimus3

Corticosteroids
4-7

Adapted from Grassberger et al 1999; Zuberbier et al 2001; Meingassner et al 1997; Cheer et al 2001; Goodwin et al 1986; Chandrabose et al 1978.

TCI, topical calcineurin inhibitor; TCS, topical corticosteroids.

1. Grassberger M, et al. Br J Dermatol. 1999 Aug;141(2):264–73. 2. Zuberbier T,et al. J Allergy Clin Immunol. 2001 Aug;108(2):275–80. 3. Cheer SM, Plosker GL. Am J Clin Dermatol. 2001;2(6):389–406. 4. Goodwin JS, et al. J Clin Invest. 1986 Apr;77(4):1244–50. 5. Chandrabose KA, et
al. Proc Natl Acad Sci USA 1978;75:214–7. 6. Greaves MW. Postgrad Med J 1976;52,631–3. 7. Barnes PJ. Immunol Allergy Clin N Am 25 (2005) 451–68.
27
 Indication: atopic dermatitis
• Tacrolimus ointment: moderate to severe AD
– 0.1% ointment: > 16 year
– 0.03% ointment: 2-15 year
• Pimecrolimus 1% cream: mild to moderate AD
– Approved in pts > 2 yrs
– Extensively studied in infants 3–23 mos
• American Academy of Dermatology’s guideline, EFTAD/EADV guideline:
– Recommend off-label use of pimecrolimus 1% cream and tacrolimus 0.03%
ointment for children < 2 yrs with mild to severe atopic dermatitis
 Effective long-term management of AD 29

Long-term goals
of management ACUTE or REACTIVE TREATMENT
include:1 Effective in treating flares
• Long-term flare Reactive treatment of AD flares, using a stepwise approach
prevention based on disease severity1 to obtain remission

• Avoidance of
side effects

PROACTIVE THERAPY
More effective in treating recurrent disease

Long-term maintenance treatment of previously affected areas,

using less-frequent, low-dose anti-inflammatory therapy to prevent
subsequent flaring1,2

1. Wollenberg et al. JEADV. 2018;32:657–82. 2. Eichenfield LF, et al. J Am Acad Dermatol. 2014;71(1):116–32.
 2013 Asia-Pacific Consensus: Treatment by disease stage 30

Treatment of Poorly
Controlled AD*
Reactive management Proactive management • Emollients
1 • Avoidance of irritant/trigger
Poorly factors
1 controlled flare • Rescue therapy:
–Corticosteroids
–Wraps/soaks
–Antibiotics
2 Flare
Treatment of flares
Severity

2 • Emollients
• Avoidance of irritant/trigger
Minimal factors
3 or no flare • Prompt use of site-specific
TCS or TCIs
3
Proactive therapy for
minimal
or no flares
• Emollients
Remission Adapted from Rubel et al 2013. • Avoidance of irritant/trigger
factors
• TCIs
• Hotspot therapy
*Experienced physicians/dermatologists may consider using oral corticosteroids to help control an acute flare.
Rubel D, et al. J Dermatol 2013 Mar;40(3):160–71.
Thai CPG of Atopic Dermatitis 2014
 AAD 2014: Non-pharmacological +/- anti-inflammatories 32

Non-pharmacologic
interventions
• Moisturisers
• Wet wrap therapy
• Proper bathing practices

Topical Corticosteroids Use of Topical Calcineurin

Inhibitors
• For those with poor response to good
skin care and regular use of emollients • For acute and chronic treatment
alone
• For children and adults
• Consider patient age, area of the body,
• For use on actively affected areas as a
xerosis, patient preference and cost of
steroid-sparing agent
medication
• For patients <2 yrs old with mild to
• Proactive, intermittent (1–2x/per week)
severe disease
on areas that commonly flare
• Proactive, intermittent use (2–3x/week)
• Potential for topical and systemic side
on areas that commonly flare
effects should be considered,
particularly in children
Adapted from: Eichenfield et al 2014.

Tacrolimus ointment is not indicated for the treatment of AD in children <2 years old. Tacrolimus is not indicated for mild AD. Tacrolimus should be applied once a day twice weekly for
maintenance treatment.
Eichenfield LF, et al. J Am Acad Dermatol. 2014;71(1):116–32.
 JDA 2016: Induction and Maintenance Therapy 33

Definitive diagnosis

• Initial assessment of disease history, extent and severity

• Explanation of the disease and treatment goals

Considerations for treatment adherence

• Concrete explanation regarding drug therapy/skin care and patient
education
Flare

Continuation of moisturizers/skin care

Remission Induction therapy
(no signs or symptoms) Use TCS or TCI
Remission
Adjuvant
therapy
• Oral
Therapy for Proactive therapy antihistamines
complications Proactive, intermittent use of TCS or TCI • Trigger
avoidance
• Psychosomatic
approach

Severe refractory disease

Potent TCS or combination therapies

Adapted from Saeki et al 2016.

JDA, Japanese Dermatological Association; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid.
Saeki H, et al. J Dermatol. 2016;43(10):1117–45.
 EFTAD/EADV 2018 and EDF 2018: Long-term stepwise 34

approach based on SCORAD or symptom persistence

“Atopic dermatitis is a chronic condition. • For every phase, additional therapeutic

Therefore, treatment has to be planned with options are given
a long-term perspective and special attention • Add antiseptics/antibiotics in cases of
must be given to long-term safety aspects.” superinfection

MILD: MODERATE: SEVERE:

BASELINE:
SCORAD <25 SCORAD 25-50 SCORAD >50
Basic Therapy
or transient AD or recurrent AD or persistent AD

• Education • Reactive therapy with • Proactive therapy with • Hospitalization

• Emollients, bath oils, TCS or depending on topical tacrolimus or class • Systemic
• Avoidance of allergens local cofactors II or III TCS immunosuppression
• TCIs • Wet wrap therapy, UV therapy
• Antiseptics • Psychosomatic counseling,
• AEGIS underwear climate therapy

EFTAD, European Task Force on Atopic Dermatitis; EADV, European Academy of Dermatology and Venereology; EDF, European Dermatology Forum; SCORAD, Scoring Atopic Dermatitis;
TCS, topical corticosteroids; UV, ultraviolet.
1. Wollenberg A, et al. J Eur Acad Dermatol Venereol. 2018;32:657–82. 2. EDF. EDF-Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis). Available at:
www.euroderm.org/edf/index.php/edf-guidelines/category/5-guidelines-miscellaneous. Accessed 24 May 2018.
 EFTAD/EADV 2018 and EDF 2018: 35

MILD: MODERATE: SEVERE:

BASELINE:
SCORAD <25 SCORAD 25-50 SCORAD >50
Basic Therapy
or transient AD or recurrent AD or persistent AD

• Education • Reactive therapy with • Proactive therapy with • Hospitalization

• Emollients, bath oils, TCS or depending on topical tacrolimus or class • Systemic
• Avoidance of allergens local cofactors II or III TCS immunosuppression
• TCIs • Wet wrap therapy, UV therapy
• Antiseptics • Psychosomatic counseling,
• AEGIS underwear climate therapy

EFTAD, European Task Force on Atopic Dermatitis; EADV, European Academy of Dermatology and Venereology; EDF, European Dermatology Forum; SCORAD, Scoring Atopic Dermatitis;
TCS, topical corticosteroids; UV, ultraviolet.
1. Wollenberg A, et al. J Eur Acad Dermatol Venereol. 2018;32:657–82. 2. EDF. EDF-Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis). Available at:
www.euroderm.org/edf/index.php/edf-guidelines/category/5-guidelines-miscellaneous. Accessed 24 May 2018.
 AD: Proactive treatment
 Long-term, low-dose intermittent application of anti-inflammatory
therapy to previously affected skin with daily application of emollients to
unaffected area
 Anti-inflammatory drugs:
 TCI; tacrolimus 2-3 times weekly… decrease number of flares,
increase days free of topical anti-inflammatory use
 TCS; twice weekly, safely for at least 20 wks
 Fluticasone propionate 0.05% cream
 Methylprednisolone aceponate 0.1% cream
 Reduce risk of flare, lengthening the time to relapse
 Significantly decrease eczema flares
 Benefits of long-term proactive therapy 37

RT RT RT Proactive treatment RT

Inflammation
(flare)
Degree of inflammation

Visible

Flare Flare Flare

Subclinical inflammation
Invisible
No inflammation
Time

Proactive therapy reduces rates of relapse1-4

RT, reactive therapy.

1. Wollenberg et al. JEADV. 2018;32:657–82. 2. Eichenfield LF, et al. J Am Acad Dermatol 2014;71:116–32. 3. Saeki H, et al. J Dermatol 2016;43:1117–45. 4. Katayama I, et al. Allergol
Int 2017;66:230–47.
 AD patients who benefit mostly from TCI treatment

• AD affecting delicate areas of skin

• Extensive area of affected skin
• AD that is difficult to manage
• Frequent flares
• Chronic active disease
• High emotional stress
• Steroid phobia
 Off label use of TCIs
• Vitiligo
• Cutaneous lupus erythemaotsus
• Cutaneous lesion in
dermatomyositis
• Localized scleroderma
• Psoriasis (esp. facial,
intertriginous area)
• Alopecia areata
• Cutaneous Crohn’s disease
• Chronic graft-versus-host disease
• Seborrheic dermatitis
• Contact dermatitis
• Perioral dermatitis
• Granuloma annulare
• Lichen sclerosus et atrophicus
• Pemphigus
• lichen planus (oral and genital)
• Pyoderma gangrenosum
• Granulomatous rosacea
 Efficacy

• TCIs are effective for the treatment of atopic dermatitis.

– In both adults and children
– Both acutely and long term
• Improvement is seen rapidly.
• Effectiveness is maintained on a long term basis.
• The 0.1% concentration may provide additional clinical benefit compared
with the 0.03% tacrolimus ointment concentration.
 Side effects

• The most frequently occurring adverse events were skin burning and
pruritus:
– Mild, of short duration, and transient
– Occurred early in treatment esp. 1st wk
– Rarely led to treatment discontinuation
– More often in severe, extensive disease vs. mild, less extensive disease
• Other side effects: ACD, rosacea-like granulomatous reaction
 Safety
• A boxed warning: theoretical concern for risk of malignancy
– Short-term or intermediate-term (>15 yrs):
• No evidence of systemic immunosuppression
• No increased risk for malignancy

• No reports of skin atrophy at application site for any patient

• No systemic effect: immunomodulatory effect is limited to the skin
• Normally no significant systemic absorption
– Low systemic levels following application to ulcers/eroded mucosa
– Except in patients with Netherton syndrome
• Minimize or avoid natural or artificial sunlight exposure
• Precautions: apply on ulcerative area, patient receiving phototherapy
 Communication to Patients

1. Apply twice a day

2. Apply emollient 2 hour after Protopic® application
3. Do not use occlusive technique
4. Advice about side effect: burning and pruritus
5. Minimize or avoid natural or artificial sunlight exposure
 44

Topical tacrolimus

(Protopic®)

MAT-18205, date of preparation: June 2018

 Mechanism of action of tacrolimus 45

TCIs inhibit T cell activation in AD

1 TCI binds to the binding protein, FKBP1

APC

2 TCI complex binds with CaN complex1

Antigen

3 • NFAT interaction and dephosphorylation1

is blocked T cell
• NFAT remains in cytoplasm
CaN FKBP TCI

4 • IL-2, IL-3, IL-4, IL-5, GM-CSF, TNF-α NFAT

production inhibited1
• T-cells remain inactive

Adapted from Castro et al 2006.

APC, antigenten-presenting cell; CaN, calcineurin; NFAT, nuclear factor of activated T-cells; FKBP, FK506 binding protein; TCI, topical calcineurin inhibitor.
Castro APBM. J Pediatr (Rio J) 2006;82(5 Suppl):S166–72.
 Topical tacrolimus has multiple effects on AD pathogenesis 46

Topical tacrolimus

Inhibition of calcineurin1

↓ T cell activation and ↓ FcϵRI IgE receptors

proliferation2 in dendritic APCs3,4 ↓ Release of inflammatory
mediators
Up-regulation of filaggrin
(e.g., histamine)
and loricrin genes7
from mast cells and
↓ Proinflammatory cytokine basophils5,6
↓ Antigen recognition
production (e.g., IL-2)

↓ INFLAMMATION ↑ BARRIER FUNCTION

Hypothesized Adapted from Rico et al 2002; Wollenberg et al 2001; Siracusa et al 2013; Sengoku et al 2000; Simpson et al 2005; Leo Laboratories Limited 2016.

AD, atopic dermatitis; APC, antigen-presenting cells such as inflammatory dendritic epidermal cells and Langerhans cells.
1. EU SmPC of Protopic(r), 30 Jan 2018. 2. Simpson D, et al. Drugs 2005;65:827–58. 3. Rico MJ, Lawrence I. Allergy Asthma Proc 2002;23:191–7. 4. Wollenberg A, et al. J Allergy
Clin Immunol 2001;107:519–25. 5. Siracusa MC, et al. J Allergy Clin Immunol 2013;132:789–8. 6. Sengoku T, et al. Int J Immunopharmacol 2000;22:189–201. 7. Chittock J, et al.
Acta Derm Venereol 2015;95:653‒8.
 Topical tacrolimus promotes skin barrier function in AD 47

Effects of topical tacrolimus on skin barrier function in AD

Avoids skin atrophy1

No effect on skin collagen synthesis1,2

↑ Skin thickness2

↓ Protease activity vs baseline3

Skin barrier Atopic Immune system
dysfunction dermatitis dysfunction
↓ TEWL vs TCS3

↑ SC capacitance (hydration)3

Maintained SC cohesion better than TCS3

Lower skin pH vs TCS3

Adapted from Reitamo et al 1998; Kyllönen et al 2004; Chittock et al 2015.

AD, atopic dermatitis; AUC, area under the curve; SC, stratum corneum; TEWL, transepidermal water loss; TCS, topical corticosteroids.
1. Reitamo S, et al. J Invest Dermatol 1998;111:396–8. 2. Kyllönen H, et al. Br J Dermatology 2004;150:1174–81. 3. Chittock J, et al. Acta Derm Venereol 2015;95:653‒8.
 Topical tacrolimus is associated with a favorable effect on 48

skin barrier function compared with TCS in quiescent AD

Improved stratum corneum cohesiona Transepidermal water loss (TEWL)

indicating increased mechanical strength

500 20
Betamethasone valerate 0.1% **
Pre-BMVc
* 15 Tacrolimus 0.1%
400 Post-BMVc

Change in TEWL from baseline

10 Barrier
Cumulative protein (µg cm-2)

Pre-TACo **
* function
300 Post-TACo 5 decreases

0 **
200 *
*
-5
100
-10
*
Barrier
0 -15
function
increases

*p<0.001 *p<0.05; **p<0.001

5 10 15 20 5 10 15 20
Tape strip number Number of tape strips

Adapted from Danby et al 2014.

AD, atopic dermatitis; AUC, area under the curve SC, stratum corneum; TCS, topical corticosteroid.
20 volunteers with quiescent atopic dermatitis; Tape-stripping is a validated technique to non-invasively measure the structural integrity of the SC.
aProtein mass removed by tape stripping
Danby et al. Br J Dermatol 2014;170:914–21,
 Topical tacrolimus is associated with a favorable effect 49

on skin hydration and pH compared with TCS in quiescent AD

Skin hydration: significant increase in capacitance, Skin pH: TCS treatment increased skin pH to a greater
an indirect measure of hydration, observed with extent than tacrolimus (p<0.01)
tacrolimus vs TCS (p<0.05) and untreated skin • Skin pH following TCS was significantly greater than
(p<0.01) that of untreated skin (p<0.001)

p<0.01 p<0.001 p<0.01

p<0.05
50 6
Relative capacitance units

5
40
4

Skin-surface pH
3
30
2
1
20
0

10

0 Untreated Betamethasone Tacrolimus 0.1%

Untreated Betamethasone Tacrolimus 0.1% valerate 0.1%
valerate 0.1%

Adapted from Chittock et al 2015.

17 volunteers with quiescent AD; AD, atopic dermatitis; TCS, topical corticosteroid
Chittock et al. Acta Derm Venereol 2015;95:653‒8
 Topical tacrolimus is associated with a significant reduction in 50

skin protease activity compared with TCS in quiescent AD

Caseinolytic protease activity: suppressed Trypsin-like protease activity: inhibited significantly

significantly more with tacrolimus than TCS (p<0.05) by tacrolimus vs untreated skin (p<0.05)
and vs baseline (p<0.05)

p<0.01 p<0.05

6 p<0.05 2.5
Caseinolytic specific activity

Trypsin-like specific activity

5 2.0
4
1.5
3
(nU/ug)

(nU/ug)
1.0
2
1 0.5
0 0

Untreated Betamethasone Tacrolimus 0.1% Untreated Betamethasone Tacrolimus 0.1%

valerate 0.1% valerate 0.1%

Adapted from Chittock et al 2015.

Data indicate that tacrolimus is able to reduce protease activity

associated with quiescent, asymptomatic AD

17 volunteers with quiescent AD; AD, atopic dermatitis; TCS, topical corticosteroid
Chittock et al. Acta Derm Venereol 2015;95:653‒8
 Favorable effect of topical tacrolimus on TEWL, skin 51

hydration and lipids compared with TCS in active AD

TEWL: significant reduction in TEWL
with tacrolimus (but not mometasone
furoate cream) vs baseline (p=0.021)
after 10 days of therapy
Skin hydration: significant doubling Skin lipids: significant fourfold
of skin moisture with tacrolimus after increase in the length of intercellular
10 days of therapy (p=0.017) vs lipids with tacrolimus vs baseline and
constant skin moisture with mometasone furoate cream after 10
mometasone furoate cream days therapy (p<0.001)

p<0.001
50
70 240 p<0.001
p<0.05 p<0.05
40 60 200 n.s. p<0.001
n.s. n.s.

Nm ICLL/1,000 nm2 ICS

50
30 n.s. n.s. n.s. n.s. 160
40
120
20
g/m2*h

30
Mean

80
10 20
10 40
0
0 0

Baseline After 10 days Baseline After 10 days Baseline After 10 days

of treatment of treatment of treatment

Mometasone furoate cream Tacrolimus 0.1% ointment

Adapted from Dähnhardt-Pfeiffer et al 2013.

Data indicate that tacrolimus significantly reduces TEWL and increases skin
hydration after 10 days of treatment in patients with active AD

20 adult patients with active AD; NS, not significant; AD, atopic dermatitis; TCS, topical corticosteroid; TEWL, transepidermal water loss
Dähnhardt-Pfeiffer et al. JDDG 2013;11:437‒43
 Topical tacrolimus targets both cutaneous inflammation 52

and skin barrier dysfunction

Tacrolimus
reduces cutaneous
inflammation…1-4

…while
promoting skin barrier
function.5,6

Adapted from Fleischer et al 1999; Rico et al 2002; Wollenberg et al 2001; Simpson et al 2005; Kyllonen et al 2004; Chittock et al 2015.

TCS, topical corticosteroids

1. Fleischer AB. J Allergy Clin Immunol 1999;104:S126–S130. 2. Rico MJ, Lawrence I. Allergy Asthma Proc 2002; 23:191–7. 3. Wollenberg A, et al., J Allergy Clin Immunol
2001;107:519–25. 4. Simpson D, et al. Drugs 2005; 65:827–58. 5. Kyllonen H, et al. Br J Dermatol 2004;150:1174–81. 6. Chittock J, et al. Acta Derm Venereol 2015;95:653‒8.
 Tacrolimus 0.03% is effective for the treatment of AD in 53

pediatrics
Change from baseline for total score for signs of AD and EASI score (LSM)

Total Score EASI Score

Study Randomised, 0 0
design double-blind,
-2
vehicle-controlled -1
-4
trial -2
-6

Reduction in Total Score

Reduction in EASI Score

-3 -8
Patients 351 children -10
-4
(2–15 years old) -12
with moderate to -5
-14
severe AD -6
-16

-7 -18
Treatment Tacrolimus ointment
**
0.03% or 0.1%* or **
vehicle, bid on
affected areas for 12 **p<0.001

weeks Vehicle Tacrolimus 0.03% ointment

AD, atopic dermatitis; EASI, Eczema Area and Severity Index; LSM, least mean square.
*Tacrolimus 0.1% ointment is not indicated for the treatment of AD in children <16 years old.
Paller A, et al. J Am Acad Dermatol 2001;44:S47–57.
 Tacrolimus 0.03% is more effective than hydrocortisone 54

acetate 1% in AD in pediatrics

% Median improvement in mEASI mAUC in children with moderate to severe AD

70
**
Study Multicentre, randomised, **p<0.001

Median improvement in mEASI mAUC

design double-blind, 60

parallel-group trial
50

Patients 560 children with moderate 40

(%)
to severe AD
30

Treatment Tacrolimus ointment 20

0.03% or 0.1%* or
hydrocortisone acetate 10
1% ointment, bid on
affected areas for 3 weeks 0
Tacrolimus 0.03% Hydrocortisone acetate
ointment 1% ointment
Adapted from Reitamo et al 2002.

AD, atopic dermatitis; mAUC, mean area under the curve; mEASI, modified Eczema Area and Severity Index.
*Tacrolimus 0.1% ointment is not indicated for the treatment of AD in children <16 years old.
Reitamo S, et al. J Allergy Clin Immunol. 2002;109:539–46.
 Tacrolimus 0.03% is as effective as methylprednisolone 55

aceponate 0.1% in AD in paediatrics

% Patients with clear/almost clear AD (by IGA score) after 3 weeks

70

Study Randomised

Patients with clear/almost clear AD (%)

design comparative trial 65

60
Patients 265 children and
adolescents with
severe to very 55
severe flare of AD
50

Treatment 0.1% MPA ointment

vs 0.03% tacrolimus 45

ointment for 3 weeks

40
Tacrolimus 0.03% ointment MPA ointment 0.1%
Adapted from Bieber et al 2007.

AD, atopic dermatitis; BSA, body surface area; EASI, Eczema Area and Severity Index; IGA, investigators’ global assessment; MPA, methylprednisolone aceponate.
Bieber S, et al. Allergy. 2007;62(2):184–9.
 Tacrolimus 0.03% significantly improves QoL in AD in 56

pediatrics

LSM Change in QoL scores from baseline in Children (5-15 years old) after 12 weeks

Symptoms School or Personal Total QoL

and feelings Leisure Holiday relationships Sleep Treatment score
Study Three 12-week, 0
design randomised, double-
blind studies (pooled) -5

-10
Patients 985 patients with
p=0.092
moderate to severe -15
Improvement

AD, including 323

p=0.009
paediatric patients -20
p=0.020

-25 p=0.000
Treatment Tacrolimus ointment
(0.03% for children -30
and 0.1% for adults)
versus vehicle -35 p=0.000
p=0.000
ointment p=0.000

-40
Vehicle Tacrolimus 0.03% ointment

Adapted from Drake et al 2001.

AD, atopic dermatitis;, LSM, least square mean; QoL, quality of life.
Results for tacrolimus 0.1% ointment not shown.
Drake L, et al. J Am Acad Dermatol. 2001;44(1 Suppl):S65-72.
 Meta-analysis: Tacrolimus 0.03% is more effective than 57

mild potency TCS in AD in paediatrics

Tacrolimus Steroids Risk ratio Risk ratio
Study of subgroup Weight
Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI

Tacrolimus 0.03% 1x/day vs hydrocortisone acetate 1% 2x/day

Reitamo 2004 57 205 28 206 100.0% 2.05 (1.36, 3.08)

Subtotal (95% CI) 205 206 100.0% 2.05 (1.36, 3.08)

Tacrolimus 0.03% 2x/day vs hydrocortisone acetate 1% 2x/day

Reitamo 2002b 73 189 29 185 51.0% 2.46 (1.69, 3.60)

Reitamo 2004 77 210 28 206 49.0% 2.70 (1.83, 3.97)

Subtotal (95% CI) 399 391 100.0% 2.58 (1.96, 3.38)

Tacrolimus 0.03% 2x/day vs steroids moderate potency 2x/day

Reitamo 2002a 73 193 96 186 63.1% 0.73 (0.58, 0.92)

Sikder 2005 2 15 10 15 36.9% 0.20 (0.05, 0.76)

Subtotal (95% CI) 208 201 100.0% 0.45 (0.13, 1.57)

Tacrolimus 0.03% 2x/day vs methylprednisolone 0.03% 1x/day

Beiber 2007 91 136 86 129 100.0% 1.00 (0.85, 1.19)

Subtotal (95% CI) 136 129 100.0% 1.00 (0.85, 1.19)

Total events 91 86

Heterogeneity: Not applicable

0.01 0.1 1 10 100
Test for overall effect: Z=0.04 Favours steroids Favours tacrolimus
(p=0.97)
Adapted from Cury Martins et al 2015.
Test for subgroup differences: Chi2=40.43, df=3(p<0.00001). I2=92.6%

Outcome: % Patients with Physician’s assessment of global response of improvement, clear or excellent

AD, atopic dermatitis; TCS, topical corticosteroids.

Cury Martins J, et al. Cochrane Database Syst Rev. 2015 Jul 1;(7):CD009864.
 Safety profile

58
MAT-18205, date of preparation: June 2018
 Minimal systemic exposure with topical tacrolimus in AD 59

in pediatrics patients

Systemic exposure to tacrolimus in children with moderate to severe AD (n=39)

vs. oral tacrolimus (0.15 mg/kg/12 hr) for transplant patients

500
• 92% of blood samples <1 ng/ml
400 concentration
Tacrolimus AUC (ng·h/mL)

300 • 17% of samples <0.025 ng/ml

(lower limit of quantification)
200
• Systemic exposure increased with
100
size of treated BSA
Transplant
0 Patients with AD patients • Absorption decreased as skin
lesions healed
Day 4 Day 14

Tacrolimus 0.1% ointment bid Oral tacrolimus

Adapted from Harper et al 2005.

AD, atopic dermatitis; AUC, area under the curve; BSA, body surface area.
Tacrolimus 0.1% ointment is not indicated for the treatment of AD in children <16 years old.
Harper J, et al. J Invest Dermatol. 2005;124:695–9.
 Application site reactions with tacrolimus ointment 60

• Burning and pruritus are most

common adverse events with Combined analysis
topical tacrolimus1
Application
Tacrolimus Pimecrolimus
• Majority are mild to moderate site reaction
in intensity1
• Transient (significantly decreased Burning 10.9% 9.6%
after 1 week of use)1,2
• Reduced prevalence as AD
improves2 Pruritus 7.0% 7.1%
• Similar incidence between topical
tacrolimus and pimecrolimus3 Pain 2.1% 1.5%

Erythema 0.9% 1.7%

Adapted from Paller et al, 2005.

Tacrolimus 0.1% ointment is not indicated for the treatment of AD in children <16 years old. Tacrolimus ointment is not indicated for mild AD.
1. EU SmPC of Protopic®, 30 Jan 2018. 2. Koo JY, et al. J Am Acad Dermatol 2005;53:S195–205. 3. Paller AS, et al. J Am Acad Dermatol 2005;52:810–22.
 No increased risk of cutaneous infections with topical 61

tacrolimus

12-week pooled adjusted incidence rates of cutaneous infections

N=1554 adult and AD in paediatrics patients from 5 clinical trials

No significant increase in cutaneous infections

between tacrolimus 0.03%/0.1%* vs vehicle

25
Tacrolimus ointment 0.03% bid
(n=328)
20
Tacrolimus ointment 0.1%* bid
Incidence rate (%)

(n=327)
15
Vehicle (n=328)
p=0.001
10

p=0.01
5

0
Total Skin Dermato- Folliculitis Herpes Furunculosis Warts Pustular
cutaneous infections phytosis simplex exanthem
infections

Adapted from Fleischer et al 2002

*Tacrolimus 0.1% ointment is not indicated for the treatment of AD in children <16 years old.
Fleischer AB, et al. J Am Acad Dermatol. 2002;47:562–70.
 Topical tacrolimus does not affect vaccine efficacy in AD 62

in pediatrics patients

Study Hofman et al (2006)1 Stiehm et al (2005)2

Patients Children aged 2 to 12 years with moderate to Children aged 2 to 12 years (n=23) with
severe AD (n=232) and 44 children without AD moderate to severe AD
as control

Vaccine Meningococcal protein-conjugate vaccine PPSV-23

Methods • Multicentre, randomised, controlled trial • Open-label, noncomparative study

• Patients treated with tacrolimus 0.03% • Patients treated with tacrolimus 0.03%
ointment or hydrocortisone ointment ointment bid for 7 weeks
• Immunised after a week of AD treatment • Immunised after 3 weeks of tacrolimus
treatment

Results Response rate (patients with SBA titre > 8) was • Protective pneumococcal titers to all 12
97.5% for tacrolimus, 99.1% for hydrocortisone serotypes were observed 70% of children
and 97.7% for control (p=NS) postvaccination
• 91% of patients had >4-fold increase in titer
for >4 of 12 serotypes

AD, atopic dermatitis; PPSV-23, 23-valent pneumococcal polysaccharide vaccine; SBA, serum bactericidal antibody; NS, non-significant.
1. Hofman T, et al. Arch Dis Child 2006;91:905–10. 2. Stiehm ER, et al. J Am Acad Dermatol 2005;53(2 Suppl 2):S206–13.
 Long-term safety of TCIs in children with AD 63

Long-term TCI use does not increase AEs vs TCS and does not cause skin atrophy

Range of AE rates in long-term (>12 weeks) pediatric clinical trials

Tacrolimus Pimecrolimus Low/Mid Potency

0.03% (n=524) 1.0% (n=4,455) TCS (n=1,999)

Discontinuation due to 2-5% 0.4-5% 0.7-3%

AE

Cutaneous AEs
Bacterial infection 1-10% 0-12% 0-10%
Viral infection 0.4-18% 0-25% 4-23%*
Fungal infection NR 3%* 0-0.7%*
Atrophy NR NR 8-12%

Systemic AEs
Bacterial infection 3-16% 0-22% 11-17%*
Viral infection 2%* 2-17% 1-17%
Respiratory tract infections 4-90%* 0.7-35% 4-32%
Gastrointestinal AEs 38%* 3-32% 21-31%*

AD, atopic dermatitis; AE, adverse event; NR, not reported; TCI, topical calcineurin inhibitors.
*Only one trial reported rates for the AE.
Long-term safety data were summarized descriptively; statistical analyses were not performed due to the inconsistency in reporting of data between included trials.
Siegfried EC, et al. BMC Pediatr 2016;16:75.
 Body of evidence on TCIs and skin malignancies 64

Body of scientific evidence does not support a causal increase

in the risk of skin malignancies with the use of TCIs

Study Study details Results

Legendre et • Meta-analysis • AD patients had an increased risk of lymphoma

al (2015)1 • 24 cohort and • AD severity was a significant risk factor
case-control studies • Topical steroids and TCIs are unlikely to be
related to lymphoma risk

Siegfried et al • Systematic review • No incident lymphoma reported

(2015)2 • 27 long-term (≥12 • “A decade’s worth of clinical experience,
week) clinical trials in epidemiological data, postmarketing surveillance
patients <12 years with and adverse event database monitoring have
AD failed to demonstrate a causal relationship
• n=5,825 between TCI use and malignancy…”
TCI-treated patients

Deleuran et al Danish Registry including Vs controls, TCI patients had no increased risk of:
(2016)3 34,921 children with TCI • Melanoma (OR 0.46; 0.15–1.46)
exposure • Leukaemia/lymphoma (OR 1.46; 0.94–2.28)

TCI, topical calcineurin inhibitors; AD, atopic dermatitis; OR, odds ratio.
1. Legendre L, et al. J Am Acad Dermatol 2015;72:992–1002. 2. Siegfried EC, et al. BMC Pediatr 2016;16:75. 3. Deleuran M, et al. Acta Derm Venereol 2016;96:834–45.
 Summary
• TCS are the mainstay of the treatment of inflammatory skin diseases.
• If not abused, TCS are very safe.
• TCIs are topical macrolide immunomodulators which provide anti-
inflammatory effects without side effects of TCS.
• TCIs are safe and effective for the treatment of atopic dermatitis.
– In both adults and children
– Both acutely and long term management
– Patients who benefit mostly from TCI treatment: AD affecting delicate areas
of skin, difficult to manage, extensive area of affected skin, frequent flares,
chronic active disease, steroid phobia
• Off label use: vitiligo, seborrheic dermatitis, contact dermatitis, psoriasis,
alopecia areata, cutaneous lupus erythemaotsus, cutaneous lesions in JDM,
localized scleroderma
65
Thank you for your attention