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Original Paper

Dermatology 2013;227:37–44 Received: January 4, 2013


Accepted after revision: April 19, 2013
DOI: 10.1159/000351559
Published online: August 31, 2013

Pulse Corticosteroid Therapy for Alopecia


Areata in Children: A Retrospective Study
Rivka Friedland a Rotem Tal c Moshe Lapidoth a, b, e Alex Zvulunov d
Dan Ben Amitai d, e
a
Department of Dermatology and b Laser Unit, Department of Dermatology, Rabin Medical Center,
c
Day Care Unit and d Pediatric Dermatology Unit, Schneider Children’s Medical Center of Israel, Petach Tikva,
and e Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Key Words (29%) a partial response and 8 (33%) no response. Of the 16


Childhood · Alopecia areata · Corticosteroids · Pulse therapy responders, 13 (81%) relapsed at 9.5 ± 12 months after the
last course; 3 patients had side effects, none of which were
severe. Three positive prognostic factors were identified:
Abstract short disease duration (≤6 months), younger age at disease
Background/Objective: Alopecia areata may occur at any onset (<10 years) and multifocal disease (as opposed to se-
age, though usually before the age of 20 years. Treatment vere, diffuse variants). Conclusions: Careful patient selection
often consists of systemic steroids administered as high- is necessary to achieve maximal benefit from pulse cortico-
dose bolus infusions. This study sought to investigate the steroid treatment for alopecia areata in children.
effectiveness and side effects of intravenous high-dose pulse © 2013 S. Karger AG, Basel
corticosteroids in children with alopecia areata and to iden-
tify prognostic factors for successful treatment. Methods:
Patients treated with pulse corticosteroids for alopecia area- Introduction
ta in 2001–2008 at the day care unit of a tertiary pediatric
medical center were identified by computerized file search Alopecia areata (AA) is characterized by sudden,
and clinical treatment and outcome data were collected. patchy nonscarring hair loss, usually on the scalp although
Results: The sample included 24 children (16 female, 8 male) any hair-bearing skin may be involved. The hairless patch-
with a mean age of 8.5 ± 4.6 years at diagnosis; 8 (33%) had es are typically round or oval, smooth and well circum-
multifocal disease,10 (42%) multifocal disease with ophiasis, scribed. They may present in the frontal or parietal scalp
4 (17%) alopecia totalis and 2 (8%) alopecia universalis. Nail or in the form of a band that extends from the posterior
involvement was noted in 9 patients (38%). Mean duration occiput to the temporal areas bilaterally (ophiasis). AA
of disease was 22 ± 27 months. Patients were treated with may progress from single or multifocal patches to com-
8 mg/kg body weight intravenous methylprednisolone on 3 plete loss of scalp hair (alopecia totalis, AT) or further, to
consecutive days at 1-month intervals. After a mean of 5.65 loss of all body hair, including eyebrows, eyelashes, other
± 1.95 courses, 9 patients (38%) had a complete response, 7 facial hair and pubic hair (alopecia universalis, AU).
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© 2013 S. Karger AG, Basel Moshe Lapidoth, MD, MPH


1018–8665/13/2271–0037$38.00/0 Laser Unit, Department of Dermatology
Kainan University

Rabin Medical Center


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E-Mail karger@karger.com
Petach Tikva 49202 (Israel)
www.karger.com/drm
E-Mail alapidot @ netvision.net.il
The estimated life-time risk of AA in the general pop- Table 1. Baseline characteristics of children with AA treated with
ulation is 1.7% [1, 2]. Though AA may occur at any age, high-dose pulse methylprednisolone
onset is usually (60% of cases) before the age of 20 years
Characteristics
[2]. The pathogenesis is still unknown, but increasing ev-
idence points to a reversible tissue-restricted autoim- Sex
mune process [3–5]. A hallmark of the acute phase of AA Female 16 (66.6)
is a peribulbar lymphocytic infiltrate, rich in helper T Male 8 (33.3)
lymphocytes [6]. The hair follicle is not destroyed, there- Ethnicity
Jewish 12 (50)
fore, so there is a potential for regrowth. Arab 11 (46)
Patients usually have several episodes of hair loss and Bedouin 1 (4)
regrowth during their lifetime. Recovery may be com- Age at onset, years 8.5 ± 4.6 (2.7 – 17.2)
plete, partial or absent [7]. The prognosis depends on sev- Severity
eral factors. Poor prognostic factors include the early on- Multifocal 8 (33)
Ophiatic 10 (42)
set of disease, ophiasis, diffuse disease, positive family his- AT 4 (17)
tory and atopic dermatitis. AU 2 (8)
Systemic corticosteroids are one of the various treat- Duration of disease, months 22 ± 27 (0 – 103)
ment approaches described to induce remission in pa- Comorbidities
tients with AA. To avoid side effects, the drug is admin- Hypothyroidism 1 (4)
Atopic dermatitis 1 (4)
istered as high-dose bolus infusions [8–10]. The aim of Asthma 1 (4)
the present study was to investigate the effectiveness and Psoriasis 1 (4)
safety of high-dose pulse corticosteroid therapy in chil- Family history
dren with AA and to identify prognostic factors for suc- AA 2 (8)
cessful treatment. Asthma 3 (12.5)
Atopic diathesis 3 (12.5)
Hypothyroidism 2 (8)
Vitiligo 1 (4)
Methods Values are presented as number with percentage or mean ± SD
with range.
A computerized file search was conducted in the day care unit
of a tertiary university-affiliated pediatric medical center to iden-
tify all patients treated for AA with methylprednisolone from 2001
to 2008. Patient referral to the day care unit was from the pediatric
dermatology unit. The range of years was limited in order to allow
a significant long-term follow-up. All patients were treated with a
protocol of 8–10 mg/kg body weight (up to 500 mg/dose) intrave- Results
nously on 3 consecutive days at 1-month intervals. All patients
underwent thyroid function tests and a subdermal screening test A total of 24 children met with the study criteria. Their
for tuberculosis infection (Mantoux test). Patients were clinically demographic and clinical data are summarized in table 1.
assessed by a pediatric dermatologist every 1–2 months. The group included 16 girls and 8 boys (female:male ratio
Medical charts were reviewed and data on clinical characteris-
tics, number of steroid courses, response to treatment, and follow- 2:1) with a mean age of 8.5 ± 4.6 years (range 2.7–17.2)
up were recorded. Complete response was defined as full hair re- at diagnosis; 12 (50%) were Jewish, 11 (46%) Arab and
growth at all alopecic sites, partial response as hair regrowth in part 1 (4%) Bedouin. Associated comorbidities included hypo-
of the alopecic areas, and no response as absence of all evidence of thyroidism, asthma, atopic dermatitis and psoriasis, in
hair regrowth. Mild relapse was defined as hair loss of up to 10% 1 patient (4%) each. Of the 24 patients, 5 (20%) had a fam-
of scalp hair and severe relapse as loss of all hair regrowth or worse.
The study was approved by the local institutional review board. ily history of autoimmune diseases, 2 of AA (8%), 2 of
hypothyroidism (8%) and 1 of vitiligo (4%); 6 patients
Statistical Analysis (24%) had a family history of atopic diseases – asthma and
The distribution of response to treatment by demographic and atopic dermatitis (3/24, 12% each).
clinical variables was analyzed with the χ2 test. Variables associ- At the time of referral for pulse corticosteroid therapy,
ated with complete response on univariate analysis (p < 0.2) were
entered into a multivariate logistic regression model with complete 8 patients (33%) had multifocal disease without ophiasis,
response as the binary outcome. All analyses were performed with 10 (42%) had multifocal disease with ophiasis, 4 (17%)
the SPSS for Windows, version 13 (SPSS Inc.). had AT and 2 (8%) had AU. There was no significant dif-
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38 Dermatology 2013;227:37–44 Friedland /Tal /Lapidoth /Zvulunov /


       

DOI: 10.1159/000351559 Ben Amitai  


Kainan University
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Table 2. Treatment-associated parameters

Patient Sex Age at presen- Previous Treatment Pulses, Regrowth F-U, Relapse Delay to re-
No. tation, years treatment delay, months n with pulses, n months lapse, months

Multifocal
1 F 3.9 TS 3 3 CR (2) 1 No –
2 M 3.8 TS, PM, TC, SA 0 5 CR (5) 40 Yes 3
3 M 9.3 TS, PM, TC, SA 2 3 CR (2) 6 Yes 4.5
4 F 10.8 TS 31 6 CR (6) 24 Yes 8
5 F 5.3 TS, IL 22 6 CR (6) 29 Yes 24
6 F 16.1 TS, IL, DT 4 9 PR (2) 25 Yes 7
7 F 17.2 TS, DT 2 6 NR 7 – –
8 F 14.2 TS, PM, SA, DT 11 8 NR 38 – –
Multifocal + ophiasis
9 F 4.7 TS, TC, DT 1 4 CR (2) 43 Yes 1
10 M 4.9 TS 48 6 CR (3) 12 Yes 8
11 M 5.6 TS, PM 6 8 CR (2) 68 Yes 36
12 F 14.0 TS, IL, DT 10 3 PR (3) 1 No
13 F 10.5 TS, IL, DT 1 7 PR (4) 43 Yes 24
14 F 3.3 TS, IL, DT 70 5 PR (2) 42 Yes 2
15 M 9.9 TS, TC 26 10 PR (5) No Yes 0
16 F 5.0 TS, IL 60 10 NR 17 – –
17 F 4.0 TS 103 2 NR No – –
18 F 2.7 TS, IL, TC 26 5 NR No – –
AT
19 F 6.3 No 4 4 CR (4) 1 Yes 1
20 M 10.9 TS, IL 56 10 PR (10) 26 No –
21 F 3.5 TS 6 3 NR No – –
22 M 11.8 TS 38 8 NR No – –
AU
23 M 11.3 TS, IL, DT 14 7 PR (4) No Yes 0
24 F 14.7 TS 13 2 NR No – –

CR = Complete regrowth; F-U = follow-up period after treatment; NR = no response; PR = partial regrowth; TS = topical corticoste-
roids; IL = intralesional injection of corticosteroids; DT = dithranol; SA = squaric acid; TC = tacrolimus; PM = pimecrolimus.

ference in age at diagnosis between patients with multi- monitored on days 1–3 of each therapy course before and
focal AA or more severe clinical variants (p = 0.181); 9 immediately after intravenous application of corticoste-
patients (38%) had nail involvement (6 with ophiatic AA, roids. Weight and height were also measured during
2 with AT and 1 with AU). None of the patients with treatment courses. After a mean of 5.83 ± 1.95 treatment
multifocal disease without ophiasis had nail involve- courses (range 2–10), 9 patients (38%) had a complete
ment. response, 7 (29%) a partial response and 8 (33%) no re-
Table  2 summarizes data regarding treatment, re- sponse. Response to treatment was first documented after
sponse and follow-up. Mean duration of disease until a mean of 3.87 ± 2.19 cycles (range 2–10). In 3 of the 16
pulse corticosteroid therapy initiation was 23 ± 27 months responders there was no relapse; 1 patient was free of dis-
(range 0–103). All patients also underwent thyroid func- ease during a follow-up period of 26 months; 2 patients
tion tests and a subdermal screening test for tuberculosis enjoyed remission for 1 month before they were lost to
infection (Mantoux test), and were then treated with a follow-up. In 13 of the 16 responders (81%), the disease
protocol of intravenous methylprednisolone (8 mg/kg relapsed at a mean of 9.5 ± 12 months (range 0–36) after
body weight – up to 500 mg/dose) on 3 consecutive days the last treatment course; 2 patients had a mild relapse
at 1-month intervals. Blood pressure and heart rate were and were treated with topical steroids and 8 patients pre-
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Pulse Corticosteroids for Pediatric Dermatology 2013;227:37–44 39


Alopecia Areata DOI: 10.1159/000351559
Kainan University
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Color version available online
sented with severe relapse; 6 of them were referred for
another course of intravenous pulse methylprednisolone, 100

Complete recovery rate (%)


1 was treated with intralesional injections of corticoste- 90
80
roids and 1 refused further treatment. Data were missing 70
for 3 patients. Among the 6 patients who were treated 60
50
with a second course of pulse intravenous methylpred- 40
nisolone, 4 had a good response to the second course (3 30
20
after 3 months of treatment and 1 after 2 months) and 10
1 had a partial response (after 3 months of treatment). 0
Age <10, Age <10, Age –10, Age –10,
Among the 5 responders of the second course, there was multifocal AA other AA multifocal AA other AA
follow-up for another 2 years for only 1 patient; 5 months (n = 4) (n = 10) (n = 4) (n = 5)
after the end of the second course a relapse was noted, and
he was treated topically with dithranol and tacrolimus Fig. 1. Complete recovery rates and 95% CIs (Fisher’s exact test) of
with no response. Data were missing for another patient; AA, according to type and age at onset (years).
3 patients had side effects of methylprednisolone, none of
which were severe (verrucae, gastritis, abdominal pain).
Table 3 summarizes the distribution of selected patient
Table 3. Prognostic factors for complete response to treatment:
characteristics according to response to treatment. On univariate analysis
univariate analysis, there was no effect of any of the de-
mographic or clinical parameters on response rate. Fur- Complete recovery rate p value
ther analysis of complete response versus partial and no n %
response revealed an association of short disease duration
(<6 months vs. ≥6 months) with an increased likelihood Sex 0.397
of complete response (p = 0.033). Male 5/15 33.3
The rate of complete response was highest in the sub- Female 4/8 50.0
Age at onset, years 0.072
group of patients with multifocal disease (5/8, 62%), fol- ≤4 4/8 50.0
lowed by the more severe variants of ophiatic AA (3/10, 5–9 4/6 66.7
33%), AT (1/4, 25%) and AU (0). These differences were ≥10 1/9 11.1
not significant on univariate analysis (p = 0.214). How- Ethnicity 0.379
ever, after adjusting for age at onset on multivariate logis- Jewish 5/12 41.7
Arab 3/10 30.0
tic regression (fig. 1), multifocal AA was found to be as- Bedouin 1/1 100.0
sociated with a significantly increased likelihood of com- Severity of disease 0.310
plete recovery compared to the other types of alopecia Multifocal 5/8 62.5
(odds ratio (OR) = 48.82, 95% CI: 0.95–2,517.65, p = Ophiatic 3/9 33.3
0.05). Younger age at onset (<10 years) was also associ- AT 1/4 25.0
AU 0/2 0.0
ated with significantly higher chances of complete re-
Nail change 0.371
sponse (fig. 1), with an OR of 0.62 per year (95% CI: 0.41– Yes 7/14 50.0
0.95, p = 0.03). No other variables were significantly as- No 2/9 22.2
sociated with complete response in the multivariate AA duration, months 0.033
model. ≤6 6/10 60.0
>6 2/12 16.7

Discussion

AA is a cosmetically disturbing disease that affects palliative, not curative. There is no evidence from ran-
young people. Therefore, many treatment modalities domized controlled trials that steroids, whether topical,
have been applied such as topical, intralesional or sys- intralesional or systemic, are of benefit in treating AA [4].
temic corticosteroids, psoralen and ultraviolet A, contact Nevertheless, systemic corticosteroids have been consid-
immunotherapy, anthralin, minoxidil, topical calcineu- ered to be the most effective treatment and the treatment
rin inhibitors and cyclosporine [11, 12]. All of them are of choice for AA [11], but their prolonged administration
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40 Dermatology 2013;227:37–44 Friedland /Tal /Lapidoth /Zvulunov /


       

DOI: 10.1159/000351559 Ben Amitai  


Kainan University
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a b

Fig. 2. Alopecia subtotalis. a Before treatment. b After 6 sessions.

Table 4. Clinical data on 39 children, previously reported, treated with corticosteroid pulse therapy for AA

Seiter [4], 2001 Kiesch [14], 1997 Hubiche [18], 2008 Sharma [20], 1998 Summary

Number of patients 4 7 12 16 39
Female 3 3 8 11 25
Male 1 4 4 5 14
Age, years 14 – 16 (15) 4 – 10 (7.7) 1 – 15 (6.75) 3 – 18 (11)
Duration of disease, months ND 3 – 44 1 – 96 (28.7) 2 – 96 (20.3)
Scalp affected, % 60 – 100 (80) 30 – 100 (57.8) 20 – 100 (64) 30 – 100 (50.6)
Treatment IV MP IV MP IV MP oral P
Number of pulses ND ND 2 – 3 (2.58) 1 – 8 (4.1)
Response, n
Excellent 2 5 7 9 23 (59%)
Good 3 1 4 (10%)
None 2 1 2 5 10 (26%)
Side effects ND 6 none none 14 none
1 abdominal pain 1 headache
1 epigastric pain
Follow-up, months 12 12 12 – 83 (44.2) 6 – 60 (25)
Relapse none 1 relapse all relapsed 5 relapsed 18/22 (81.8%)
(10 – 100%) (4 patches, 1 total)

Values in parentheses are means unless otherwise indicated. ND = No data; P = Prednisolone; MP = methylprednisolone.

is associated with severe adverse effects. In 1975 Burton intravenous [4, 10, 14–19] or oral [9, 20–22], were pub-
and Shuster [13] were the first to administer a single lished. Four of these studies [4, 14, 18, 20] concern a pe-
2-gram intravenous methylprednisolone pulse in 22 pa- diatric population (a total of 39 patients) (table 4). In the
tients with AA; however, only 3 (14%) had satisfacto- present study, 16 patients (67%) exhibited terminal hair
ry hair regrowth. Thereafter, several additional studies regrowth, but only 38% had a complete response (equiva-
showing a beneficial effect of pulse corticosteroids, either lent to a cosmetically acceptable appearance) (fig. 2, 3).
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Pulse Corticosteroids for Pediatric Dermatology 2013;227:37–44 41


Alopecia Areata DOI: 10.1159/000351559
Kainan University
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a b

Fig. 3. AA. a Before treatment. b After 6 sessions.

The wide range of treatment success rates in the litera- AU subtype is associated with earlier age at onset, longer
ture is probably attributable to differences in the proto- duration of disease, susceptibility to autoimmune diseas-
cols used and in patient selection methods. Be that as it es and low probability of response to treatment [24]. In
may, it is likely that outcome was affected by the presence our study disease severity was found to predict therapeu-
of certain factors. Short disease duration (≤6 months) tic response, as patients with multifocal disease had a
was a positive prognostic factor in our study and was also higher likelihood to respond to treatment than patients
associated with favorable results in previous studies in with ophiatic AA, AT or AU. A poor treatment response
both adults [19] and children older than 12 years [20]. in patients with the severe variants has also been suggest-
The better response associated with early disease may be ed by previous studies [4, 10, 15, 17, 19].
explained by findings of fewer functional follicular struc- The safety of high-dose corticosteroids in children is
tures and some follicular scarring in patients with long- an important consideration. Concerns have been raised
standing AA [23]. Therefore, selecting patients in the ear- that corticosteroids may expose patients with AA to a risk
ly stages of disease may be crucial to their ability to re- of deleterious side effects without altering the long-term
spond to corticosteroid pulse therapy. It should be noted, course of the disease [25]. Prolonged use of corticoste-
however, that Seiter et al. [4] reported higher response roids can lead to Cushingoid habitus, electrolyte distur-
rates in patients with long-term disease than in patients bances, cardiovascular effects, glucose intolerance, diabe-
treated during their first episodes of AA. Younger age at tes mellitus, loss of bone density and osteoporosis with
disease onset (<10 years) was also associated with a better concomitant vertebral fracture, muscular weakness, de-
prognosis in our cohort. Similarly, Sharma and Muralid- layed healing, peptic ulcer, cataract, glaucoma, psychiat-
har [20] observed a better response to therapy in their ric disturbances and increased risk of infections [26]. In
group aged 3–11 years (71%) than in patients aged 12–18 children, corticosteroids can also lead to growth retarda-
years (50%). However, Im et al. [19] did not find any ef- tion [27]. Discontinuation of therapy is followed by a pe-
fect of age on outcome. These epidemiological studies in riod of compensatory growth [28].
large populations are needed to clarify the impact of both Pulse therapy by the administration of suprapharma-
disease duration and age. cological doses of corticosteroid is cumulatively less toxic
AA is classified into several clinical subtypes: multifo- than sustained steroid treatment at lower quantitative
cal and ophiatic AA, AT and AU. The more severe AT/ dosage [29], but is still associated with a spectrum of ad-
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DOI: 10.1159/000351559 Ben Amitai  


Kainan University
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verse reactions in children, among which volatile behav- treatment is needed in severe AA after the success of ini-
ior is the most frequent. The nonbehavioral adverse reac- tial intervention. Friedli et al. [10] report that a second
tions include headache, abdominal complaints, pruritus, pulse given several months after the first one might be ef-
vomiting and hypertension [30]. Most symptoms were fective when relapse occurs, even in a previously partially
transient in duration, mild in severity, and required no responding patient. Indeed, in our cohort, 4/6 patients
medical treatment [31]. In the group described in the benefited from a second course. Combining pulse thera-
present study, only 3 patients had adverse effects of treat- py with low-dose oral cyclosporine [32] or methotrexate
ment, all of which were mild, and none required cessation [33, 34] may also increase probability of long-term remis-
of treatment. Previous studies reported similar findings sion.
[4, 8, 9, 15–17, 19–22]. In conclusion, this retrospective study confirms the ef-
Considering the risks related to high-dose pulse corti- fectiveness of pulse corticosteroids in the treatment of
costeroids, clinicians should consider risk-efficacy ratio children with AA. Careful patient selection is necessary
regarding the number of cycles that the patient received to achieve the maximal benefit of treatment. Success rates
before determining treatment failure. Surprisingly, we are higher in patients with a short duration of disease (≤6
did not find any consideration for this practical question months), young age at onset and multifocal AA as op-
in the literature. In our cohort, initial hair growth was posed to ophiatic AA, AT or AU. These findings may help
documented after a mean of 3.87 ± 2.19 cycles (range clinicians identify responders to corticosteroid pulse
2–10). Based on this limited data, it seems reasonable to therapy. The present study also adds evidence for short-
offer a patient up to 6 cycles and to withdraw the treat- term safety, but the long-term safety is still unknown.
ment if there is no response. More information is needed to define the optimal timing
Pulse corticosteroids are effective in patients with AA, and course of steroid pulses to avoid chronic toxicity and
but their benefit is maintained only as long as the patient obtain maximum benefit. Given the high relapse rates
continues treatment [18]. In the present study, the major- found after cessation of treatment, we suggest that pa-
ity of responders (81%) relapsed after treatment was dis- tients and parents be informed of the option to combine
continued. Other studies in which patients were treated other immunosuppressive drugs to achieve long-term re-
with intravenous pulse methylprednisolone reported re- mission.
lapse rates of 16.7–38% within 4–70 months of follow-up
[4, 17, 19]. Findings for oral pulse prednisolone were sim-
ilar [9, 21]. The highest reported relapse rate (74%) was
Disclosure Statement
found in 2006 by Kurosawa et al. [16] in patients treated
with daily oral dexamethasone. Thus, as in other chronic The authors have no conflicts of interest. No funding was re-
autoimmune/inflammatory skin diseases, maintenance ceived for this study.

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44 Dermatology 2013;227:37–44 Friedland /Tal /Lapidoth /Zvulunov /


       

DOI: 10.1159/000351559 Ben Amitai  


Kainan University
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