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British Journal of Dermatology

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Diphenylcyclopropenone in patients with alopecia areata. A critically appraised topic DOI: 10.1111/bjd.14040

Summary

Clinical scenario

Aim To assess the efficacy and safety of topical diphenylcyclopropenone (DPCP) in patients with alopecia areata. Setting and design Study selection, data extraction, risk of bias assessment and analyses were carried out independently by two authors. The quality of evidence was rated with Grading of Recommendations Assessment, Development and Evaluation (GRADE). No randomised trials were identified, but 11 case series, conducted in dermatology departments in the Netherlands, UK, Iran, Italy, Egypt and Greece were included. Study exposure Patients with mainly extensive and long-lasting alopecia totalis and universalis were treated. Most often one side of the scalp was treated with DPCP whilst the other side received no treatment. Treatment duration varied from 4 to 48 months with a follow up of 6 to 36 months. Outcomes Outcomes included quality of life, patient satisfaction, adverse events, treatment effect and duration of remission. Results Eleven studies, with sample sizes of 18–139 comprising 500 patients, were retrieved. Our critical outcomes quality of life and patient satisfaction, were not or hardly addressed. In about half of the patients DPCP appeared to be effective, with transient side effects such as contact eczema, blistering, oedema of eyelids, headache and flu-like symptoms. If treatment was satisfactory the effect was maintained for more than a year. The overall quality of the evidence was rated very low. Conclusion There is very low quality evidence for the effectiveness and safety in extensive resistant alopecia areata. Well-designed and well-conducted randomised controlled trials, with subsequent adequate reporting, including high-quality descriptions of all aspects of methodology are required.

A 19-year-old woman who has suffered from extensive alopecia areata (around 50% of scalp affected) for almost 25 years has been treated with topical and intralesional corticosteroids in an outpatient dermatology clinic. She has experienced insufficient improvement and wants to know, before starting to wear a wig, if diphenylcyclopropenone could be an effective and safe treatment.

Background Alopecia areata (AA), with a lifetime prevalence of 2% in the U.S.A., is one of the most common autoimmune diseases affecting adults and children.1,2 It is characterized by one or more circumscribed patches of nonscarring hair loss on the scalp.2 Although AA can resolve spontaneously, it is known to be a cosmetic burden, with a high impact on quality of life; therefore, effective treatment options are required.3,4 If treated, the first steps in treatment most often consist of topical or intralesional corticosteroids. Unfortunately, AA is difficult to treat and corticosteroids often give unsatisfactory results. Immunotherapy is one of the possible treatment modalities, and diphenylcyclopropenone (DPCP) has been used since 1983 as a topical immunotherapy to treat AA. DPCP is a strong potent contact allergen, and hair growth is stimulated by inducing a contact allergy. Around 98–99% of patients can be sensitized.5 Based on a survey among Dutch dermatologists, it is known that DPCP is still regularly used in clinical practice.6 The question is whether DPCP can, based on the existing evidence, be recommended for the treatment of AA.

Literature search A medical librarian (J.L.) performed a comprehensive search in Ovidâ MEDLINE, OVIDâ Embase, the Cochrane Central Register of Controlled Trials and the non-MEDLINE subset of PubMed (10 July 2014) (Appendix S1; see Supporting Information). All articles were screened for relevance with regard to the clinical question. Controlled trials, studies with a control group and within-participant (half-head) studies with > 15 patients were included. No language restriction was applied. Systemic comedication, which may have had an impact on AA, was considered an exclusion criterion.

Question

Outcome parameters

Is topical diphenylcyclopropenone effective and safe for patients with extensive alopecia areata?

We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the qual-

896

British Journal of Dermatology (2015) 173, pp896–909

© 2015 British Association of Dermatologists

Putting papers into practice 897

Fig 1. Flowchart literature results. AA, alopecia areata; DPCP, diphenylcyclopropenone; pt, patients. *No controlled trials, study with control group or half-head study.

ity of the evidence for the effectiveness and safety of DPCP. GRADE represents a transparent and systematic process, and is used for producing high-quality guidelines.7 Beforehand, dermatologists and patients, during a focus group session and with the use of survey results, evaluated outcome parameters and rated them according to GRADE as ‘critical’, ‘important’ or ‘not important’.6,8 We chose to replace ‘not important’ with ‘less important’ because during the focus group session it was agreed that all outcome measures were of importance. Critical outcomes were ‘change in quality of life’, ‘patient-reported improvement’ and ‘proportion of participants for which adverse events were a reason to stop’. Important outcomes were ‘total number of adverse events’, ‘duration of remission’ and ‘> 50% hair regrowth’. ‘Complete remission’ and ‘regrowth of vellus hair’ were considered less important.

Risk of bias and data extraction The risk of bias was assessed independently by two authors (R.K. and E.J.v.Z.) using the Cochrane Collaboration risk of bias tool.9 Although this tool is mainly used for randomized controlled trials (RCTs), it can also be applied to controlled trials, where, for assessing selection bias, a clear description of the disease and comparability of the groups, confounding factors need to be considered. Data extraction was performed by the same two authors independently and summarized using a structured and pretested data extraction form, and any disagreements were resolved by discussion. A GRADE ‘summary of findings (SoF)’ table was made using GRADEpro.10 The © 2015 British Association of Dermatologists

quality of the evidence for each predefined outcome was rated as high, intermediate, low or very low.11–13

What evidence is included in this critically appraised topic? The titles and abstracts of 438 articles were screened, of which 40 studies were selected for full-text reading; finally, 11 studies met the inclusion criteria (Fig. 1).14–24 Study characteristics The 11 studies comprised 500 patients. Ten studies were conducted in adults or adults and children, and one study included only children.14 No RCTs were identified. Ten studies treated one side of the scalp with DPCP and compared it with no treatment on the other side of the scalp (half-head studies).14–23 A single study compared DPCP vs. no treatment and tacrolimus 01% vs. placebo.24 A variety of AA types was included in the studies, mainly extensive and long-lasting alopecia totalis and alopecia universalis. The treatment protocols used in the individual studies were similar: sensitization of forearm skin with 0001% DPCP, increasing the dose (to a maximum concentration of 2000% DPCP) until mild contact dermatitis was elicited, with mild erythema and pruritus lasting for 24 h followed by application of DPCP to the scalp once a week or once every 2 weeks. A summary of the study characteristics and key results is presented in Table 1. British Journal of Dermatology (2015) 173, pp896–909


open-label

(1989)16

Observational

study, HH,

U.K.

et al.

Ashworth

regrowth; 16/27

risk factors (sex, age of

(2) no treatment

on adequate

13/22 responders relapsed

nail changes or other autoimmune diseases)

untreated side Follow-up 6–12 months

sensitization (n = 2) 12/18 completed 30 weeks:

gel 1–2 times daily NB: after 20 weeks DPCP extended to untreated side

regrowth after 20 weeks

Tretinoin side: no

nonresponders

response’, 9/12 were

3/12 experienced ‘a

(n = 2), loss of

weekly; (2) tretinoin 025%

of eyebrows

also had regrowth time consuming

clearly, 1/3 responders severe dermatitis (n = 1),

Response not stated

50% of patients

hair regrowth in

Eyebrow and body

untreated side

extended to other

all others had DPCP

No effect in five patients;

Comment

1/18; 5/17 were dropouts:

No sensitization in

DPCP (0001–2000)

measurement not clear)

(method of

Clinical evaluation

alopecia universalis

First 20 weeks: (1)

30 weeks

with nail changes

Only negative correlation

(n = 5)

hyperpigmentation

eczema (n = 6),

increasing concentration of

alopecia universalis

Alopecia totalis or

of regrowth

(n = 11), severe blistering/

Side-effects in 19/27: lymphadenopathy

after clinical signs

or pregnancy

experienced 10–90% partial hair regrowth

duration, type of AA,

CVD, severe disease

onset, atopy, disease

NB: if response, DPCP treatment extended to

contraception; no

Alopecia totalis and

aged 5–72 years

n = 18 (sex unknown),

90–100% hair

Assessment of possible

–2000%) weekly;

of reproductive age

Extended AA

6/27 experienced


concentration DPCP (0001

≥ 10 years; women

nonresponders

1 dropout, 5/27 were

Results

25 years

open-label

(method of

Clinical evaluation

Outcome

(1) Increasing

6–12 months

(length and type)

Interventions

hair; age

> 40% loss of scalp

n = 28 (16 female/12 male), mean age

criteria

In-/exclusion Patients

study, HH,

Observational

Iran

Aghaei

(2005)15

Methods

Country

Study

Table 1 Characteristics of included studies and summary of results

898 Putting papers into practice


© 2015 British Association of Dermatologists 31/45 relapsed during follow-up

to be nonresponders NB: if response within 3– 6 months, or sooner, DPCP extended to untreated side

> 6 months; no pregnant or lactating women; no oral

No correlation found

No side-effects in group 1 Unknown number of patients had severe eczema and one

NB: if response in group 2, other side was also treated

was reversible)

(unknown if this

developed vitiligo

good (n = 1)

combination of (1) and (2)

group 3: poor (n = 2),

one half of scalp; (3)

DPCP-treated side); regrowth)

(0001–1000%) weekly on

hair regrowth), good

doses); (2) increasing

DPCP

good (n = 1) (only at

none, poor (< 20%

(50 mg kg–1 daily in three

(> 20–100% hair

group 2: poor (n = 1),

three-point Likert scale:

(1) Inosine pranobex

good result (n = 0);

Group 1: poor or

concentration of DPCP

Alopecia totalis

Only group

> 12 months

Alopecia totalis

2 treated with

not stated)

open-label

(1991)18

(sex and age

n = 33

study, HH

Observational

(contact eczema in neck and face)

9/54 had side-effects

CVD

grade 3 (n = 15),

grade 4 (n = 20),

corticosteroids; no

Clinical evaluation by

grade 1 (n = 1)

of TPO antibodies)

6 months, patients deemed

AA treatment for

6 months

grade 2 (n = 9),

changes and presence

If no response within

for 12 months; no

45/54 were responders:

Overall response was low

treatment success

2 years after

disease duration, nail

(2) no treatment

regrowth of hair

lasting AA

were followed up for

other reason (n = 1)

predictors (sex, atopy,

(0001–2000%) weekly;

loss or no

treated for 2 years or

side-effects (n = 4),

Extended and long-

open-label Assessment of possible

Unclear if patients were

efficacy (n = 5),

Comment

10 dropouts:lack of


male, rest unknown), > 25% scalp hair

MHN gradinga

Clinical evaluation using

Results

mean age 27 years

2 years

Outcome

(1) Increasing

Extended and

n = 64 (15 female/12

(length and type)

Interventions

long-lasting AA

criteria


study, HH,

Observational

Methods

Hutchinson

Berth-Jones and

U.K.

Greece

Avgerinou et al.

(2008)17

Country

Study

Table 1 (continued)




(2005)20

Firooz et al.

Iran

> 30% loss of scalp

n = 56

previous 6 months; women of reproductive age on adequate contraceptives; no CVD or severe disease

Chronic and extended AA

40 : 60 10/25 grade 4 responders relapsed Side-effects: contact dermatitis in face and neck (n = 2), oedema of eyelids

deemed to be nonresponders NB: if response was seen, DPCP extended to untreated side Follow-up for 6–18 months

were grade 3–4 5/24 relapsed

predictors (sex, age of onset, atopy, disease duration, type of AA, nail changes and presence of other autoimmune diseases)

(0001–2000%) weekly; (2) no treatment NB: if response, DPCP treatment extended to untreated side

> 1 year

extended AA

diseases

or other autoimmune

atopy, nail changes

duration of AA, sex,

No correlation with

24/47 responders

(n = 1)

complete improvement

residence (n = 3),

(n = 1), changing

Chronic and

assessment of possible


open-label

regrowth for

female/14 male),

study, HH, mean age 23 years

(n = 4), side-effects

9 dropouts: no effect

reaction (n = 52) (1) Increasing

MHN grading;a


Anagen/telogen ratio

6 months, patients were

4–48 months

3 (n = 11)

If no response within

(n = 3), mild eczematous

grade 2 and grade

(2) no treatment

36/52 responders: grade 4 (n = 25),

anagen : telogen ratio


reaction; 16 nonresponders

4 dropouts: generalized

Results

(0001–2000%) weekly;

MHN grading;a


Outcome

(1) Increasing

6–12 months

(length and type)

Interventions

hair and/or no hair

> 25% loss of scalp

therapy in the

mean age 23 years

n = 56 (33

systemic or local

30 male),

open-label

Observational

no treatment with

(26 female/

hair in > 1 year;

criteria


study, HH,

Observational

Italy

Cotellessa

et al. (2001)19

Methods

Country

Study

Table 1 (continued)

whole scalp treated in 47/56

23/47 were grade 1–2;

treated on whole scalp

nonresponders, rest

Almost 30% were

Comment




et al. (2011)25

Hunter

(1996)21

Egypt

type of AA, severity of AA and nail changes)

treatment extended to untreated side

pruritus (n = 16)

Biopsy with

(2) no treatment

Group B: 1 responder with complete regrowth; 4 grew vellus hair; 20

(tacrolimus vs.

placebo)

CD8 expression

no change in

Decreased CD4 expression;

were nonresponders

increased CD8 expression

Decreased CD4 expression;

open-label

8 nonresponders

01%; (2) placebo

4/25 had vellus hair growth;

with 10–90% regrowth,

Group B: (1) tacrolimus

immunohistochemistry

90–100% hair regrowth)

(0001–2000%) weekly;

previous 6 months 12 months

complete regrowth,

(0 = no effect; 3 =


treatment in

3/25 were responders

responders with

four-point Likert scale

Group A: 10/25 were

Group A: (1) increasing

Clinical evaluation with

sleep due to scalp

(n = 41), impaired

No systemic

18 months

spot (n = 46),

36 months

lymphadenopathy

mild eczema at sensitization

Follow-up for 18–

vitiligo (n = 1),

(n = 1), EEM (n = 1),

(n = 2), blistering

A and B

on control side for groups

No clinical improvement

what relapse rate was

eczematous response

unsatisfying result; unclear

Side-effects: generalized

patients had a cosmetically

Unknown how many

Comment

responders (grade 1–4)

nonresponders; 32/48

1 dropout; 16/48 were

Results

study, HH,

observational

Severe AA

17 male (mean age:

(DPCP vs. no

group B:

group B: eight female/

open-label 24 years)

(mean age 21 years);

study, HH,

therapy);

female/15 male

Severe AA

atopy, disease duration,

NB: if response, DPCP

n = 50 (group A: 10

onset, atopy, familial

(2) no treatment

become pregnant

predictors (sex, age of

(0001–2000%) weekly;

planning to

AA

assessment of possible

MHN grading;a


Outcome

pregnant or


(1) Increasing

12–30 months

(length and type)

Interventions

26 years

women not

Age ≥ 18 years;

n = 48 (25 female/23 male), mean age

criteria


observational

Group A:

open-label

study, HH,

Observational

(Scotland)

U.K.

Gordon

et al.

Methods

Country

Study

Table 1 (continued)




et al. (1996)14

Schuttelaar

Netherlands

U.K.

Monk

(1989)22

Country

Study

Table 1 (continued)

Alopecia totalis/

n = 18 (10 female/8

Outcome

Results

untreated side Follow-up for 12 months

no active eczema

follow-up

during 6-month

treatment effect

and maintained

complete hair regrowth

6/8 patients had

(n = 4), lymphadenopathy

(n = 4), headache

than application site

eczema at sites other

blistering (n = 1);

vesicular eruption,

contact eczema,

Side-effects: mild

hair regrowth (< 10%)

had reasonable hair regrowth, 13/25 no

regrowth


(90–100%), 4/25

Follow-up for 6 months

0–100% scalp hair

no treatment

hair regrowth

extended to untreated side

90–100%) and score

(001–200%) weekly; (2)

Alopecia totalis and AA

8/25 had complete

(0 = no effect; 3 =


mean age 11 years

open-label

sensitization

1 dropout: no

symptoms (n = 2)

influenza-like

(n = 2); minor

(n = 1); urticaria

eczema, transient

Side-effects: severe

result (after 8–20 weeks)

regrowth with

6/11 extensive hair

patient (n = 3)

lack of motivation

three-point Likert scale

Clinical evaluation by

12 male),

(1) Increasing

3–12 months

study, HH,

Children

treatment extended to

become pregnant;

n = 26 (14 female/

acceptable cosmetic


planning to

Observational

terminal hairs and

no treatment

pregnant or

severe forms of AA

(001– 200%) weekly; (2)

Lost to follow-up:

lasting AA; not


Alopecia totalis or


extended and long-

sensitization (n = 2)

Dropouts: no

27 years

(method of

Clinical evaluation

male), mean age

(1) Increasing

Treatment duration unclear

(length and type)

Interventions

open-label

universalis or

criteria


study, HH,

Observational

Methods

Comment

together

looked at all results

AA; however, we

for AA totalis vs.

Clear presentation of results

untreated side as well

was later extended to

untreated side but DPCP

Barely vellus hair on



© 2015 British Association of Dermatologists follow-up (apparently with complete regrowth during follow-up)

complete regrowth, 28/139 had partial hair regrowth, 37/139 had unsatisfactory regrowth) 30/107 with unilateral hair regrowth relapsed Side-effects: sleep impairment (n = 48),

regrowth, 2 = satisfactory regrowth, 4 = total regrowth) Patient satisfaction score 0–10 (0 = failure, 10 = excellent) Physicians’ satisfaction judged with same Likert scale

weekly; (2) no treatment NB: if response achieved, DPCP extended to untreated side Follow-up 19 months

with blistering (n = 81)

more severe eczema

headache (n = 3),

(n = 6), EEM (n = 2),

the scalp and eyelids

(n = 7), swelling of

(n = 11), urticaria

contact eczema

during 19-month

42/139 had

1 = unsatisfactory

(00000001 – 20000000%)

there were more patients

25/53 in remission

32 were nonresponders

(0 = no regrowth,

unilateral response: 14

Mean applications for

Comment

concentrations of DPCP

107/139 had a

Results

unilateral response;

Clinical evaluation with

Outcome

four-point Likert scale

(1) Increasing

> 7 months

(length and type)

Interventions

HH, half-head study; AA, alopecia areata; CVD, cardiovascular disease; DPCP, diphenylcyclopropenone; TPO, thyroid peroxidase; MHN, MacDonald, Hull and Norris; EEM, erythema multiforme. aMHN grade 1 = regrowth of vellus hair and MHN grade 4 = regrowth whole over scalp with terminal hair.

Severe AA

open-label

Severe AA

n = 139 (sex and age unknown)

criteria


study, HH,

Observational

Netherlands

Van der Steen

et al. (1991)23

Methods

Country

Study

Table 1 (continued)




achieved a satisfactory hair regrowth of 90–100% stayed in remission for 132 months. Hair regrowth of > 50% was reported in six studies in 485% of patients, with a range of 300–500% in the individual studies. Based on six studies, complete remission was seen in 328% of patients, and in four studies vellus hair regrowth was seen in only 88% of patients. The overall quality of the evidence was very low, mainly owing to limitations in study design, the high risk of bias of the individual studies and imprecision in the effect estimate (as a result of low sample size) (Table 2).

Comment

The overall risk of bias was high, mainly owing to limitations in study design (case series), lack of blinding and high dropout rates combined with per-protocol analyses. Furthermore, as soon as treatment effect was seen on the side treated with DPCP, the other half of the head was also treated, which made assessment of the control (untreated) side impossible. The studies included several types of AA; ‘hair regrowth’ was not evaluated in a consistent manner; and, in the majority of studies, follow-up was not clearly reported (Fig. 2).

In about half of patients DPCP treatment appeared to be effective. When it was effective, the overall result was good and adverse effects other than the expected contact dermatitis were transient; however, two patients developed vitiligo. If DPCP treatment was satisfactory, the duration of remission lasted > 1 year. Nevertheless, the effect shown in the published studies might be an overestimation as in four studies the dropout rate was high and per-protocol analyses were applied. In addition, follow-up was inadequately reported in most studies and we need to take into account that AA may improve and resolve spontaneously. Side-effects were probably under-reported as reasons for dropout were not always provided. During the focus group session, patients with alopecia emphasized that AA can be a burden that should not be underestimated by caretakers, and therefore they considered any worthwhile treatment response (> 50% hair regrowth) more important than ‘complete remission’.6 Also, it seemed that patients value ‘any response’ more than ‘cosmetically acceptable hair regrowth’ as the latter is rather a vague concept and cosmetically acceptable hair regrowth is different for every patient. Nonetheless, the consequence of the type of treatment which is inducing contact dermatitis in patients, also puts caregivers at risk of sensitization, a known phenomenon that has not been taken into account in our evaluation of the evidence.25 Furthermore, treatment with DPCP is time consuming for both patient and caretaker. The costs of DPCP itself are low, but the costs of safety measures in the preparation of DPCP, weekly visits to an outpatient clinic and additional care for side-effects need to be taken into consideration.

Effects of DPCP treatments

Limitations of this critically appraised topic

For a summary of the results and SoF see Tables 1 and 2, respectively. Quality of life was not assessed in any study, and patient-reported improvement was reported in only one study, providing limited information. In 3% of patients, side-effects such as blistering and severe eczema were a reason to stop further treatment. Reported adverse events included severe contact eczema (beyond the expected eczema), severe blistering, headache, influenza-like symptoms, oedema of the eyelids, urticaria and vitiligo. In four studies, 410% of participants who

Based on limitations in study design, risk of bias and imprecision due to low sample sizes, the quality of the evidence was ‘very low’. Pooling was limited because of heterogeneity in outcome data.

Fig 2. Risk of bias summary.

Critical appraisal of the evidence


Strength of this critically appraised topic The strength of this critically appraised topic is in the extensive search; the participation of patients with alopecia in determining and rating the outcome measures; and the thorough © 2015 British Association of Dermatologists


Risk of bias

Inconsistency

Indirectness

Imprecision –

Publication bias

See comments

Overall quality of evidence –

With control

Study (%)

SoF rates

–

With DPCP

event

–

Relative effect (95% CI)

Risk with control

Risk difference with DPCP (95% CI)

Anticipated absolute effects

Proportion of participants in whom adverse events was a reason to stop (critical outcome) 475 (10)e Seriousf No serious No serious No serious Undetected inconsistency indirectness imprecision ⊕⊝⊝⊝ very low owing to risk of biasf

–

15/475 (32%)

–

–

Participant-assessed satisfaction at end of treatment [critical outcome; measured with scores of 0–10 (0 = failure, 10 = excellent); better score indicated by higher values] 28 (1),b No serious No serious Seriousd Undetected ⊕⊝⊝⊝ – 28 – The mean participant Seriousc inconsistency indirectness very low assessed satisfaction at 19 months owing to risk of end of treatment in the bias, imprecisionc,d intervention groups was 77

Change in QoL compared with baseline (critical outcome: not measured) – – – – –

No. of participants (number of studies), follow-up

Quality assessmenta

Question: Is topical DPCP effective and safe for patients with extensive AA?

Table 2 Summary of findings (SoF)

15/475 participants dropped out owing to adverse events. Might be an underestimation as reasons for dropout were not always provided and per-protocol analysis was used

Limited information was provided on this outcome, by only one study: data on the 28 participants that had a satisfactory result according to physicians; only 20 of these patients gave their response, and gave a score of 77

No studies addressed this outcome

Comments



Risk of bias

Inconsistency

Indirectness

British Journal of Dermatology (2015) 173, pp896–909 Serioush

Imprecision

Duration of remission (important outcome; better indicated by higher values) 135 (4),i No serious No serious Serioush Serioush inconsistency indirectness 6–30 months

Total number of reported adverse events (important outcome) 419 (9)g Serioush No serious No serious inconsistency indirectness


Quality assessmenta


Table 2 (continued)

Undetected

Undetected

Publication bias

⊕⊝⊝⊝ very low owing to risk of bias and imprecisionf,h

⊕⊝⊝⊝ very low owing to risk of bias and imprecisionf,h

Overall quality of evidence

–

–

With control

Study (%)

SoF rates

135

213/419 (508%)

With DPCP

event

–

–



The mean duration of remission was 132 months

–

Risk with control


Of the 135 who had satisfactory regrowth, 55 (407%) stayed in remission for a mean of 132 months. The effect shown might be an overestimation as in four studies the dropout rate was high and a per-protocol analysis was used. Additionally, the follow-up was inadequately reported in most studies and we need to take into account that AA may improve and resolve spontaneously

213/419 adverse events were reported (other than expected contact eczema). Van der Steen et al. reported far more adverse events than the other studies.23 Most common adverse events were severe eczema, headache, blistering, sleep disturbances, minor influenza-like symptoms, oedema of the eyelids and urticaria. Vitiligo in two patients

Comments




Risk of bias

Inconsistency

Indirectness

Imprecision

Publication bias

Overall quality of evidence

With control

Study (%)

SoF rates

With DPCP

event


111/338 (328%) had 100% hair regrowth 12/137 (87%) had vellus hair regrowth

–

–

Comments

147/303 (485%) had partial hair regrowth; percentages ranged from 30% to 50%


–

Risk with control


DPCP, diphenylcyclopropenone; AA, alopecia areata; CI, confidence interval; QoL, quality of life. aGrading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group grades of evidence: high quality = further research is very unlikely to change our confidence in the estimate of effect; moderate quality = further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low quality = we are very uncertain about the estimate. bvan der Steen et al.23 cNo clear description of the group of participants and no blinding of physicians, participants and outcome assessors; per-protocol analysis. dLow sample size. eAghaei,15 Ashworth et al.,16 Avgerinou et al.,17 Berth-Jones and Hutchinson,18 Cotellessa et al.,19 Firooz et al.,20 Gordon et al.,21 Monk,22 van der Steen et al.,23 Schuttelaar et al.14 fNo blinding of physicians, participants and outcome assessors; attrition bias; other half of the head was treated as well, so unclear what natural course would have been. gAghaei,15 Ashworth et al.,16 Avgerinou et al.,17 Berth-Jones and Hutchinson,18 Cotellessa et al.,19 Gordon et al.,21 Monk,22 Schuttelaar et al.,14 van der Steen et al.23 hLow sample size in all studies. iCotellessa et al.,19 Gordon et al.,21 Schuttelaar et al.,14 van der Steen et al.23 jAghaei,15 Avgerinou et al.,17 Firooz et al.,20 Monk,22 Schuttelaar et al.,14 van der Steen et al.23 kAghaei,15 Avgerinou et al.,17 Cotellessa et al.,19 Hunter et al.,25 van der Steen et al.,23 Schuttelaar et al.14 lAvgerinou et al.,17 Berth-Jones and Hutchinson,18 Hunter et al.,25 Schuttelaar et al.14

Hair regrowth (> 50%) [important outcome; assessed with MacDonald, Hull and Norris scale (1–4, with higher score indicating better) or three-point Likert scale] 303 (6)j Serioush No serious No serious Serioush Undetected ⊕⊝⊝⊝ – 147/303 – inconsistency indirectness very low (485%) owing to risk of bias and imprecisionf,h Complete remission [less important outcome; assessed with MacDonald, Hull and Norris scale (1–4, with higher score indicating better) or just in percentages] 338 (6)k Serioush No serious No serious Serioush – – – 111/338 – inconsistency indirectness (328%) Regrowth of vellus hair [less important outcome; assessed with: MacDonald, Hull and Norris scale (1–4, with higher indicating better)] 137 (4)l Serioush No serious No serious Serioush Undetected ⊕⊝⊝⊝ – 12/137 – inconsistency indirectness very low, (87%) owing to risk of bias and imprecisionf,h


Quality assessmenta


Table 2 (continued)




application of the GRADE method with detailed evaluation and reporting, which included a risk of bias assessment of individual studies, as well grading the quality of evidence for each outcome taking into account any limitations in study design or execution inconsistencies in the results, indirectness of the evidence, imprecision and publication bias. The British Association of Dermatologists’ guideline on AA only included studies up to 2001 and did not perform a critical appraisal of the included studies.4 The Cochrane review on this topic included a search up to 2006 and no RCTs were available on DPCP treatment for AA.26 However, we identified a significant number of more recently published studies, which, although lacking a robust study design and with limitations in study conduct, were critically evaluated with the GRADE method, and we rated the quality of the available evidence accordingly. As AA is a common disease, the results of this critically appraised topic may be of importance for dermatologists in clinical decision making and future guidelines.

Clinical message Based on the available evidence, we conclude that there is very low quality of the evidence for the effectiveness and safety of DPCP in extensive resistant AA. In up to half of the participants it appeared to be effective and safe; however, based on studies with limitations in study design and conduct, it might be an overestimation of effect. The time-consuming aspect of the treatments for both patients and caretakers, as well as the risk of sensitization of the personnel, needs to be taken into account. Therefore, DPCP treatment is a treatment option in patients with severe and extensive AA, who show little-to-no improvement and who are motivated to undergo this treatment. DPCP should be applied by trained personnel taking adequate protective measures to minimize the risk of ‘self-sensitization’. Most studies were conducted > 10 years ago. The importance of well-designed, adequately powered and well-conducted studies has received more attention in the last 10–20 years. Practical issues for conducting a trial of DPCP in AA include lack of standardized and validated assessment of alopecia and hair regrowth, controlling for spontaneous regrowth, length of trial, and follow-up of patients. Lack of funding and the labour-intensive treatment with the risk of caregivers becoming sensitized are additional problems. Future trials should take all these considerations into account.

What did we do in light of the evidence? Our patient started on DPCP treatment and showed improvement within 3 months, with almost full regrowth of hair after 9 months. A few small bald patches remained on which she applied colour spray to camouflage them.

Funding sources None. British Journal of Dermatology (2015) 173, pp896–909

Conflicts of interest None. 1

Dutch Association for Dermatology and Venereology (NVDV), Utrecht, the Netherlands 2 Dermatology Department, Academic Medical Center, Amsterdam, the Netherlands 3 Academic Medical Center, Amsterdam, the Netherlands 4 Dermatology Department, Leiden University Medical Center, Leiden, the Netherlands E-mail: [email protected]

R.A. KUIN1 P.I. SPULS2 J. LIMPENS3 E. J. VAN ZUUREN4

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Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s website: Appendix S1. Search strategy.
