CRITICAL APPRAISAL

Reviewer:
Fenny Florentin, MD
 OBJECTIVES

• To summarize & present the evidence of Topical Tacrolimus 0.1% vs Clobetasol

Propionate 0.05% for treatment in childhood vitiligo based on a randomized double blind,
placebo controlled trial study using critical appraisal technique format.
• To infer if the results of the study are valid & applicable to our patient.
 CLINICAL SCENARIO

PROBLEM:
• 9 y/o female
• Multiple Depigmented
Macules, Well Defined, on
Periorbital area.
• Since 2 months ago

• Assessment:
Vitiligo
 THERAPEUTIC PROBLEM
Vitiligo
• Common acquired disorder where the selective destruction of functioning epidermal
melanocytes causes depigmentation of the skin.
• Affects about 1-2% of the world population
• ± 50% affected individuals develops the disease before 20 years old and ±25% prior
to the age 8 years.
• Psychologically devastating disease which is has a significant impact of quality of life
(QoL) and self-esteem.
• Clinical manifestations result from a complex interplay of genetic and immunologic
factors result in an autoimmune melanocyte destruction.

Marion Eunice B.Tamesis, MD, Joseph G. Morelli, MD; Vitiligo treatment in childhood: A state of the art
review
Pediatric Dermatology Vol 27 no 5, 437-445,2010
THERAPEUTIC PROBLEM

Jean L.Bolognia, MD, Joseph L Jorizzo, MD, Ronald P Rapini, MD, Dermatology, 2nd ed, Vol 1,
London, Mosby Elsevier,2008, p628-632.
VITILIGO: PATHOPHYSIOLOGY AT A GLANCE

•   An autoimmune destruction of melanocytes

•    An intrinsic defect in the structure and function of melanocytes
•    Defective free-radical defense(s)
•    Reduced melanocyte survival and dysregulation of melanocyte
apoptosis
•    Destruction of melanocytes by autocytotoxic metabolites, originating
from the transepidermal melanocytorrhagy due to defective adhesion
•    Membrane lipid alterations in melanocytes
•    A deficiency of unidentified melanocyte growth factor(s)
•    Destruction of melanocytes by neurochemical substances
•    A viral infection (e.g. CMV)

Jean L.Bolognia, MD, Joseph L Jorizzo, MD, Ronald P Rapini, MD, Dermatology, 2 nd ed, Vol 1,
London, Mosby Elsevier,2008, p.628-632
Guidelines for The Diagnosis and Management of Vitiligo
D.J Gawkrodger, et al
BJD 2008, 159, p. 1051-1076

Wood
lamp &/
Thyroid Photograp
Function h+
Computeri
zed image
analysis
Guidelines for The Diagnosis and Management of Vitiligo
D.J Gawkrodger, et al
BJD 2008, 159, p. 1051-1076

DLQi
Dermatology Life Quality Index
 Vitiligo Area-Scoring Index

Location Hand Units Depigmentation Total Hands Units

Hands
Upper Extremities
Trunk
Lower Extremities
Face/Neck
Feet
Body Total

Tamihiro Kawakami et al, Disease severity Indexes and Treatment Evaluation Criteria in Vitiligo,
Dermatology Research and Practice ,Volume 2011, Article ID 750342
 Vitiligo European Task Force
Extent Staging Spreading
Rules of Nine  0: normal pigmentation +1: progressive;
1: incomplete depigmentation (including  0: stable
spotty depigmentation, trichrome&  −1: regressive
homogeneous lighter pigmentation) Assessed by combining
2: complete depigmentation (may include Wood's lamp and electric
hair whitening in a minority of hairs, light examinations in a dark
<30%) room.
3:complete depigmentation plus
significant hair whitening (>30%).

Tamihiro Kawakami et al, Disease severity Indexes and Treatment Evaluation Criteria in Vitiligo,
Dermatology Research and Practice ,Volume 2011, Article ID 750342
Guidelines for The Diagnosis and Management of Vitiligo
D.J Gawkrodger, et al
BJD 2008, 159, p. 1051-1076
 Tacrolimus
 Acts as an immunosuppressant, FK506-binding protein (FKBP)
+Calcineurin →inhibit proliferation&activation of CD4+ T helper cells →
prevent dephosphorylation of the nuclear factor of activated T
cells&blocking the cascade of cytokine gene transcription.
 Inhibit mast cell adhesion→ release of mediators from mast
cells&basophils→ ↓IL8 receptor &FcεRI on Langerhans' cells
 Side effect:
 burning skin,
 pruritus,
 erythema, viral, fungal, and bacterial infections
 flulike symptoms, fever, headache, asthma, pharyngitis and rhinitis
 Minimal systemic absorbtion

Denise K. Woo et al, Topical Tacrolimus: A Review of Its Uses in Dermatology

Dermatitis. 2005;16(1):6-21, American Contact Dermatitis Society
 Clobetasol Propionate

 Superpotent Topical steroid

 Acts as inductor of phospholipase A2 inhibitory
proteins→Control biosynthesis of potent mediators of
inflammation → inhibit releasing of arachidonic acid
 Bind to the glucocorticoid receptor, which complexes,
enteres the cell nucleus &modifies genetic transcription
(transrepression/transactivation).

Stephen E. Wolverton , Comprehensive Dermatologic Drug Therapy, 2nd ed, 2008

New York, Elsevier, p.601-609
 Adverse Effects of Topical
Corticosteroids
 Hypopigmentation
 Atrophy  Purpura, stellate pseudoscars and
ulcerations
 Telangiectasia
 Aggravation of cutaneous infections
 Epidermal barrier disturbance
 Delayed wound healing
 Striae
 Contact sensitization
 Steroid rosacea
 Alteration in skin elasticity and
 Acne mechanical properties
 Perioral dermatitis  HPA axis supression
 Steroid addiction  Systemic accumulation
 Hypertrichosis
 THERAPEUTIC PROBLEM

Among Child patients with vitiligo, would topical application of tacrolimus 0.1% or
clobetasol propionate 0.05% be effective in treating the disease based on a
randomized controlled trial?
 T

A double blind, randomized,

placebo-controlled trial of
topical Tacrolimus 0.1% VS
Clobetasol Propionate 0.05%
in Childhood Vitiligo
 OBJECTIVE

 To assess efficacy and safety of these two therapies compared with

each other and with placebo.
 PATIENT POPULATION

Inclusion criteria
 Subjects 2-16 years of age
 Vitiligo involving a maximum of 20% BSA
 8-week wash out period during which topical CS,
Phototherapy, or other topical/systemic therapy were
prohibited
 PATIENT POPULATION

Exclusion criteria
 Pregnancy or lactation
 Recognized adrenal supression
 A serious chronic condition that contraindicates the use of
Tacrolimus
 Active infection at the treatment sites
 PATIENT POPULATION
100 patients randomized

Facial group Non-facial group

n = 45 n = 55

CP 0.05% T 0.1% P CP 0.05% T 0.1% P

n = 14 n = 15 n = 16 n = 19 n = 18 n = 18

Randomization based on table of random numbers

 TREATMENT PROTOCOL
Clobetasol Tacrolimus Plain Vaseline
Propionate 0.05%
0.01%

Apply twice daily, Apply twice dailly, for 6 Apply twice dailly, for 6
intermittent 2 month on-
months months
2month off-2month on

Evaluation:
TSH,Cortisol, Baseline
Vit. B12
After 2 month
levels, B-HCG
After 4 month
After 6 month
PRIMARY OUTCOME
MEASUREMENTS
(Efficacy)
 (i) Global Score
visual Analogue Scale
 CP 0.05% T 0.1% Placebo

Baseline

After Treatment

Baseline

After Treatment
 (ii) Visual Score

 Percentage of repigmentation:
Worsening
 No change
< 50 % clearing
> 50 % clearing
 Complete Clearing
 Successful response was defined as repigmentation of > 50% after
6-month treatment
SECONDARY OUTCOME
MEASUREMENTS
Clinical Observation Noted in Data
Collections Forms

 Evaluation of frequency and type of clinical

adverse effects
 Association with other autoimmune disorders
 Prevalence of spontaneous repigmentation
CRITICAL APPRAISAL
 A. Is the study valid?

B. What are the results?

C. Will the results help me in caring for my patient?

 PRIMARY VALIDITY GUIDES

1. Was the assignment of patients to treatment randomized?

2. Were all patients who entered the trial properly accounted for & attributed at its
YES.
conclusion?

b.
Randomization a.
based on table of
Was follow-up complete?
Were patients analyzed in the groups to which they were randomized?
random numbers
 100 patients randomized

Facial group Non-facial group

n = 45 n = 55

CP 0.05% T 0.1% P CP 0.05% T 0.1% P

n = 14 n = 15 n = 16 n = 19 n = 18 n = 18

CP 0.05% T 0.1 % P CP 0.05% T 0.1 % P

n = 12 n = 15 n = 14 n = 18 n = 16 n = 15
PRIMARY VALIDITY GUIDES

NO.
90 out of 100 completed the study:
30 patients from Clobetasol propionate
0.05% group
31 patients from Tacrolimus 0.1%
group
29 patients from vehicle group
Drop out rate= 10 %
.
 CP 0.05 % DROP TOUT
0.1 % RATE Placebo
2 withdrew due to 2 lost to follow up 2 lost to follow up
Tacrolimus black box 1 spontaneous
warning repigmentation
1 withdrew consent 1 withdrew due to
Tacrolimus black box
warning
1 withdrew from study
DROP-OUT RATE (DR) = Number of lost to follow-up
Total # of subjects

DR = 3/33 x 100% DR = 2/33 x 100% DR = 5/34 x 100%

DR = 9.09% DR = 6.06% DR = 14.7%

TOTAL DROP-OUT RATE = 10/100 = 10 %

Interpretation: Since the drop-out rate did not exceed 20%, the drop-out rate did not
significantly threaten the validity of our study.
  An intention to treat analysis was done.

 The results showed no statistical difference

compared to the results.
 PRIMARY VALIDITY GUIDES

2. Were all patients who entered the trial properly accounted for & attributed at its
conclusion?
a. Was follow-up complete?
b. Were patients analyzed in the groups to which they were randomized?

YES.
None of the patients switched medications.
 SECONDARY VALIDITY GUIDES

1. Were patients, their clinicians, & study personnel “blind” to treatment?

2. YES.at the start of the trial?

Were the groups similar
• Study Design: Randomized double blind, controlled trial
3. Aside from the experimental intervention, were the groups treated equally?

• The patients, primary investigator, and an independent

physician assessor were blinded of treatment group to which
patients were assigned until the study was completed.
 PROFILE AND BASELINE
CHARACTERISTICS OF PATIENTS
 SECONDARY VALIDITY GUIDES

3. Aside from the experimental intervention, were the groups treated equally?

NO.
•Methodology: Treatments were given to the patients on both
groups by the blinded investigators .
•Medication were applied with the same frequency for both
groups, but different duration of period of medication applied.
 STUDY VALIDITY

PRIMARY VALIDITY GUIDE

Randomized? YES
Adequate follow-up? YES
ITT Analysis? YES
SECONDARY VALIDITY GUIDE
Patients, clinicians, study personnel blinded? YES
Similar baseline characteristics? YES
Groups similarly treated? ?

Overall, is the study valid? YES

 A. Is the study valid?

B. What are the results?

C. Will the results help me in caring for my patient?

RESULTS
CLINICAL IMPORTANCE

1. How large was the treatment effect?

2. How precise was the estimate of the treatment effect?

 Facial Group
(responded succesfully)

CP 0.05% T 0.1% Placebo

7 people with 9 people with 2 people with

Repigmentation > 50% Repigmentation > 50% Repigmentation
3 people complete clearance 2 people complete clearance >50%

10 out of 12 11 out of 15 2 out of 16

 Non-Facial Group
(responded succesfully)

CP 0.05% T 0.1% Placebo

7 people with 9 people with -

Repigmentation > 50% Repigmentation > 50%
2 people complete clearance 2 people complete clearance

9 out of 18 11 out of 16 0 out of 16

 TREATMENT EFFECT OF
Tacrolimus 0.1% VS Clobetasol Propionate 0.05%

BASED ON OUTCOME THAT IS NO CURE

Risk value of Tacrolimus (RT) = 9/31 = 0.290
Clobetasol Propionate 0.05% (RC) = 11/30 = 0.367
Relative Risk (RR) = RT/RC = 0.290/0.367 = 0.79
Relative Risk Increase =[1- RR] = [1-0.79] x 100% = 20.9%

INTERPRETATION:
Tacrolimus 0.1% is 20.9 % more beneficial than Clobetasol Propionate 0.05%
 TREATMENT EFFECT OF
Tacrolimus 0.1% VS Clobetasol Propionate 0.05%

 Absolute Risk Increase (ARI) = (a / a + b) – (c / c + d)

= RT – RC
= 0.290 – 0.367
= 0.077x 100
= 7.7 %

Interpretation:
There is 7.7% chance that Tacrolimus 0.1% will improve the
outcome compare to Clobetasol Propionate 0.05%
 TREATMENT EFFECT OF
Tacrolimus 0.1% VS Clobetasol Propionate 0.05%

 Number Needed to Treat (NNT) = 1/ARR

= 1/0.077
= 12

Interpretation: You need to treat 12 patients to produce 1 benefit.

 TREATMENT EFFECT OF
Tacrolimus 0.1% vs Clobetasol Propionate 0.05%

Relative Risk = 0.79

95% CI (0.3839–1.6331)

Favours T 0.1% Favours CP 0.05%

Interpretation: Outcome is beneficial and result is statistically

insignificant since our Confidence Interval crossed 1 .
 Worst Case Scenario
Tacrolimus 0.1% VS Clobetasol Propionate 0.05%

BASED ON OUTCOME THAT IS NOT CURE

Risk value of Tacrolimus (RT) = 11/33 = 0.333
Clobetasol Propionate 0.05% (RC) = 11/33 = 0.333
Relative Risk (RR) = RT/RC = 0.333/0.333 =1
Relative Risk Increase =[1- RR] = [1-0.79] x 100% = 0%

INTERPRETATION:
Clobetasol Propionate 0.05% is equally harmfull with Tacrolimus 0.1%
 ADVERSE EFFECTS OF
Tacrolimus 0.1% VS Clobetasol Propionate 0.05%

BASED ON OUTCOME THAT IS HARM

Risk value of (RT) Clobetasol Propionate 0.05% = 7/30 = 0.233
Tacrolimus (RC) = 10/31 = 0.323
Relative Risk (RR) = RT/RC = 0.233/0.323 = 0.721
Relative Risk Increase =[1- RR] = [1-0.79] x 100% = 27.8%

INTERPRETATION:
Tacrolimus 0.1% is 27.8 times more harmful than Clobetasol propionate 0.05%
 ADVERSE EFFECTS OF
Tacrolimus 0.1% VS Clobetasol Propionate 0.05%

 Absolute Risk Increase (ARI) = (a / a + b) – (c / c + d)

= RT – RC
= 0.233 – 0.323
= 0.09 x 100
=9%

Interpretation:
There is 9% chance that Tacrolimus 0.1% will cause adverse
effects as compared to Clobetasol Propionate 0.05%
 TREATMENT EFFECT OF
Tacrolimus 0.1% VS Clobetasol Propionate 0.05%

 Number Needed to Harm (NNH) = 1/ARR

= 1/0.09
= 11

Interpretation: You need to treat 11 patients with Tacrolimus 0.1% to produce 1 adverse effect.
 TREATMENT EFFECT OF
Tacrolimus 0.1% vs Clobetasol Propionate 0.05%

Relative Risk = 0.723

95% CI (0.3169–1.6509)

Beneficial Harmful

Interpretation: Outcome is harmfull and result is statistically

insignificant since our Confidence Interval crossed 1 .
 A. Is the study valid?

B. What are the results?

C. Will the results help me in caring for my patient?

 APPLICABILITY

1. Can the results be applied to my patient care?

2. Were all clinically important outcomes considered?

3. Are the likely treatment benefits worth the potential harm & cost?
 PATIENT POPULATION

Inclusion criteria
 Subjects 2-16 years of age
 Vitiligo involving a maximum of 20% BSA
 8-week wash out period during which topical CS,
Phototherapy, or other topical/systemic therapy were
prohibited
 PATIENT POPULATION

Exclusion criteria
 Pregnancy or lactation
 Recognized adrenal supression
 A serious chronic condition that contraindicate with using
of tacrolimus
 Active infection at the treatment sites
 APPLICABILITY

1. Can the results be applied to my patient care?

YES.
Patient met the inclusion criteria and
none of the exclusion criteria.
 APPLICABILITY

2. Were all clinically important outcomes considered?

YES.
Repigmentation ,type of repigmentation,
and possible adverse effects were assessed
during each visit.
 APPLICABILITY
3. Are the likely treatment benefits worth the potential harm & cost?

It depends.

• Cost of Clobetasol Propionate 0.05% = P 200

• Cost of Petroleum Jelly 100g = P 20
• Cost of Tacrolimus 0.1% = P 2150
 AUTHOR’S CONCLUSION

 Both Clobetasol Propionate 0.05% and Tacrolimus

0.1% oinments offer similar benefit in pediatric
vitiligo both facial and non facial.
 The Facial lesions responded faster than nonfacial
ones .
 REVIEWER’S CONCLUSION

 Both Tacrolimus 0.1% and Clobetasol propionate 0.05% can be used in

the therapy of childhood vitiligo because of the documented increase in
pigmentation in this study.
 The documented repigmentation through time was not shown in this study
so we are not able to assess which one gives the faster response of
repigmentation.
 In the end of study, evaluation of repigmentation respond divided only
facial and non facial vitiligo but not based on pattern and coverage of BSA
which is also important to determine.
 REVIEWER’S CONCLUSION
 Despite the use of potent steroids in this study, review of literature showed that in childhood vitiligo, the youngest
age to give Tacrolimus 0.1% is 2 years old , on the other hand, Clobetasol dipropionate 0.05% is safe for 12 years
old and above.

 Even though the safety is similar in both treatments, other studies have established that with topical tacrolimus, there
was less than 4% systemic absorption, however, the use of clobetasol propionate causes abnormal cortisol level
29% of 101 subjects after 4 months of use.
Alaiti S, Kang S, Fiedler CV, et al. Tacrolimus (FK506) ointment for atopic dermatitis:a phase I study in adults and children. J Am Acad Dermatol. 1998;38:69-76
Kwinter J, Pelletier J, Khambalia A, Pope E. High-potency steroid use in children with vitiligo: a retrospective study. J Am Acad Dermatol 2007; 56:236–41.

 There should be a quantitative measure of improvement based on SCORAD based on other studies.
 REVIEWER’S CONCLUSION

 I suggest that in areas that has thin and sensitive skin (such as the
face, groin and breasts which is more prone to topical steroid side
effects, such as atrophy, telengiectasia and striae) , it is better to use
Tacrolimus 0.1% , even though results of this study showed
comparable safety profile.

Silverberg NB, Lin P, Travis L et al. Tacrolimus ointment promotes repigmentation of vitiligo in
children: a review of 57 cases. J Am Acad Dermatol 2004; 51:760–6
 REVIEWER’S CONCLUSION
 Because the study did not compare the efficacy of both treatments on segmental and acral
vitiligo (difficult to treat), I did literature search which showed that it is better to use Clobetasol
propionate 0.05%. More studies can be done to substantiate this.
Sushruta Kathria et al. Segmental vitiligo: A randomized controlled trial to evaluate efficacy and safety of 0.1% tacrolimus ointment vs
0.05% fluticasone propionate cream, Indian Journal Dermatology,2012, vol.78, p68-73

 Since the use of clobetasol propionate 0.05% more than 8 weeks may cause adverse effects, if
the use during this time period will yield unsatisfactory response, it may be prudent to shift the
medication into Tacrolimus 0.1 %

Clayton R. A double-blind trial of 0Æ05% clobetasol propionate in the treatment of vitiligo. Br J Dermatol 1977; 96:71–3.
 REVIEWER’S CONCLUSION

A longer follow up period and more subjects can be used to investigate

if any adverse effects will develop while using both medications, and
to determine which will cause faster repigmentation and is more
efficacious in specific patterns, areas and BSA affected of vitiligo.
A double blind, randomized, placebo-controlled trial of topical
. 
tacrolimus 0.1% vs clobetasol 0.05% in childhood vitiligo

N.Ho, E.Pope, M.Weinstein, S.Greenberg, C.Webster, BR. Krafchik

British Journal of Dermatology, 21 March 2011
THANK YOU