Therapy of alopecia areata with topical corticosteroid: prospective double-blind controlled assay in children

Abstracts

FUNDAMENTOS: Na alopecia areata há perda súbita e assintomática de pêlos em qualquer área pilosa do corpo. A etiologia é desconhecida, e os tratamentos propostos não costumam alterar o curso natural e imprevisível da doença. Atinge as crianças, menos responsivas às terapêuticas e mais susceptíveis às formas mais extensas. O estado atópico é considerado fator de pior prognóstico; é provável que a relação entre as duas doenças se deva às origens imunológicas, embora sejam desconhecidos seus pontos de intersecção. OBJETIVOS: Avaliar a eficácia do dipropionato de betametasona em creme a 0,05% na alopecia areata da criança e a influência da atopia na resposta terapêutica. MÉTODO: Estudo prospectivo controlado duplo cego em 35 crianças de até 12 anos portadoras de alopecia areata, atendidas no Ambulatório de Dermatologia do Instituto de Puericultura e Pediatria Martagão Gesteira - UFRJ e do Hospital Municipal Jesus, ambos no Rio de Janeiro, RJ, no período de 1996 a 1998. RESULTADOS: Das 35 crianças estudadas, 30 (85,7%) evoluíram com resposta positiva ao final de seis meses de acompanhamento. Os percentuais de resposta foram semelhantes nas terapias utilizadas - dipropionato de betametasona e placebo (p= 0,47). Dos 29 atópicos, 26 (89,6%) tiveram resposta positiva aos tratamentos. Não foi estabelecida correlação estatisticamente significativa entre a resposta terapêutica e a condição atópica (p= 0,19). CONCLUSÃO: Não houve diferença entre as respostas terapêuticas nos grupos estudados; a atopia não influenciou a resposta ao tratamento efetuado.

alopecia em áreas; corticosteróides; criança

CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION

Therapy of alopecia areata with topical corticosteroid: prospective double-blind controlled assay in children^*

Cláudia Pires Amaral Maia^I; Nurimar Conceição Fernandes^II

^IMestranda em Dermatologia da UFRJ

^IIProfessora Adjunta; Instituto de Puericultura e Pediatria Martagão Gesteira - Fac. Med. UFRJ

^{Correspondence}

SUMMARY

BACKGROUND: In alopecia areata, there is a sudden and asymptomatic hair loss in any hairy area of the body. The etiology is unknown and the treatments do not usually alter its natural and unpredictable course. It also occurs in children, who are less responsive to treatment and more susceptible to extensive forms of the disease. Atopy is considered a worsening factor in the prognosis; the relationship between both diseases is probably immunologic, but the point of connection is unknown.

OBJECTIVE: Evaluation of the efficacy of 0.05% betamethasone dipropionate (cream), and the influence of atopy in the therapeutic response.

METHODS: Prospective double-blind controlled assay in 35 children, aged up to 12 years with alopecia areata, attended at Instituto de Puericultura e Pediatria Martagão Gesteira - UFRJ and Hospital Municipal Jesus - RJ in the period 1996 -1998.

RESULTS: Thirty (85.7%) out of the 35 children studied achieved positive response after six months follow-up. The response was similar in both therapies - betamethasone dipropionate and placebo (p = 0.47). Twenty-six (89.6%) out of the 29 atopic children had a positive response. No significant correlation has been established between therapeutic response and atopy (p = 0.19).

CONCLUSION: There was no statistically significant difference between therapeutic responses; atopy did ot influence the therapeutic response.

Keywords: alopecia areata; adrenal cortex hormones; child.

INTRODUCTION

In alopecia areata (AA) there occurs an abrupt loss of body hair over a variable period of time, without any associated symptoms. The pelagic plaques can involve any pilose area and their main characteristic is the absence of alterations in the underlying skin. It involves individuals indiscriminately of all races and of both sexes, but is found more frequently in young people. The incidence in the population in general is underestimated, and there are no statistics relative to children.

The pathogenesis of AA is unknown; many etiological, genetic, emotional and, especially, immunological factors are implicated.

In spite of being a benign disease, it should be taken seriously by reason of the deep psychological trauma that it can cause the patient and his relatives, because, in extensive cases, it evokes feelings of vulnerability, inferiority and loss of self-esteem.

Several authors believe that the prognosis of AA is worse when the case begins in childhood.¹ They also pointed out that a personal or familial history of atopy is a factor in those with the worst prognosis.²

There exists now an immense therapeutic arsenal for AA; however, there is no consensus as to the best treatment. There is no concrete evidence that remission induced by drugs alters the final course of the disease. When the case is serious, the treatment to maintain adequate cosmetic hair growth is frequently of a prolonged duration.

Corticosteroids were the first effective drugs used for AA. Initially in 1952 they were used systemically³ and later topically.⁴ The possible mechanism of the action of the corticoids could be as immunosuppressants, which do not act, however, on the regrowth of normal hair. Numerous studies have reported since then various levels of therapeutic response to the various types of corticosteroids. These were usually accomplished with heterogeneous populations, and a good response was reported with betamethasone dipropionate (BD), in both adults and children.⁵

Considering the absence of controlled therapeutic studies of infantile AA in Brazil or in other countries, the authors undertook this investigation with the following objectives: to evaluate the effectiveness of 0.05% betamethasone dipropionate (BD) cream in the treatment of alopecia areata in this age group, as well as the influence of atopy in the response to treatment.

PATIENTS AND METHODS

A total of 35 children were studied in the age group of those under 12 years old who had a clinical diagnosis of alopecia areata. This was done in the outpatient dermatology clinic of the Martagã o Gesteira Institute of Child Care and Pediatrics - UFRJ and of the Municipal Hospital of Jesus, from January 1996 to February 1998.

The criteria used in the research of atopy were the patients' current and past history, personal and familial (parents and siblings) antecedents, of allergic rhinitis and bronchial asthma; and cutaneous signs of atopy (eczematoid symptoms and eczema in flexural areas).⁶

The cases were classified into partial alopecia (of hairy areas), total alopecia (AT) (of hairy areas) and alopecia universalis (AU). In cases with a doubtful diagnosis, a mycological exam was performed to exclude Tinea capitis .

The sampling was planned in accordance with the table of statistical analysis of samplings Z7, comparing proportions with dichotomous variables, and realizing a prospective, randomized double blind study. To evaluate the relationships between the variables Fisher's exact test was used with a 5% significance level (p <0.05).

The choice of BD (Diprosone ® cream) was due to the good response reported especially for children, to the safety in its use with few side effects and to the ready availability of the medication.⁵

Both BD and the placebo substance were supplied free-of-charge by Schering-Plough S.A - Chemical and Pharmaceutical Industry. The medications were put in identical tubes in two groups and numbered at random. The placebo presented the same characteristics of color, viscosity and odor as BD; such that its identification was not possible. The use of each product was made at random, according to the numbering system supplied by the laboratory as new cases of AA were attended. The cream substance was applied in a thin layer on the hairless areas twice a day, for six months. The patients were examined monthly during that period. At the end, a single observer recorded the following results: a) no repilation (without growth of hair or just vellus hair); b) initial repilation with subsequent loss (growth of terminal hair in the beginning of the treatment, that falls out again, whether or not substituted by vellus hair); c) partial repilation (growth of vellus hair whether or not covering again the whole hairless area, this is related to the growth of terminal hair that does not recover completely) - a positive response; d) complete repilation (growth of terminal hair covering the area previously totally hairless) - a positive response.

During the treatment, with the intention of moral support, all the patients as well as their relatives, who are generally deeply shocked at the disease, were directed to the department of Medical Psychology.

RESULTS

The patients' ages ranged from one to 12 years, with a mean age of 4.9 years and a standard deviation of 2.8 (Table 1); 22 (62.9%) were female, and 13 (37.1%) male (Table 2). Of the 29 atopic children, 10 (41.4%) had a personal and familial history of atopy, 10 (34.5%) had only a familial history, and seven (24.1%) had only a personal history (Table 3); 30 (85.7%) presented AA in plaques at the beginning of the study, four (11.4%) had total AA, and one (2.9%) had AA universalis (Table 4). DSeventeen patients used BD, and 18 the placebo. Of the 17 children treated with BD, 14 (82.3%) responded positively, while in the group of children treated with placebo 16 (88.8%) presented a positive response. No statistically significant differences were observed between the responses (p = 0.47) (Table 5).

Of the 24 cases with up to six months disease duration, 20 (83.3%) had responded positively by the end of six months of treatment. Four of the seven with 12 months of observation had a positive response to the therapeutics. Of the seven with more than 13 months of treatment, six (85.7%) responded positively. The duration of the disease did not influence the therapeutic response (p = 0.99) (Table 6).

Atopic and non-atopic patients were not previously selected and were distributed at random into the groups receiving medication or placebo. Of the 29 children with a personal and/or familial history of atopy, 13 (44.8%) were treated with BD, and 16 (55.1%) with the placebo. Of the six non-atopic children, four (66.6%) were treated with BD, and two (33.3%) with placebo. There was no statistically significant difference in the number of cases of atopy in the two groups (p = 0.30) (Table 7).

Among the 29 atopic children, 26 (89.6%) presented a positive response, and among the six non-atopic children, four (66.7%) responded positively to the treatment. There was no statistically significant difference in the therapeutic response between atopic and non-atopic children (p = 0.19) (Table 8).

Of the 30 children with AA in plaques, 15 (50%) were treated with BD, and 15 (50%) with placebo. Of the four children with total AA, one (25%) was treated with BD, and three (75%) with the placebo. The only case of AA universalis was treated with BD and was not considered for analysis (p = 0.35) (Table 9).

Of the 30 children with AA in plaques, 28 (93.3%) responded positively to the treatment in the six months of evaluation. Of the four children with total AA, two (50%) responded to the treatment. The only case of AA universalis failed to respond to the therapy (p = 0.06) (Table 10).

DISCUSSION

The patients' ages in the studied sampling varied from one to 12 years (Table 1), with a larger concentration in the age group of up to four years. AA can occur in any age group, although it is more common in young people under 20 years of age⁸ and especially between five and 11 years of age.⁸ There have been no prospective double-blind studies done specifically in the children population. In the literature most studies are retrospective or based on extensive questionnaires applied to patients with AA of several institutions or associations involved in the research of this disease.⁹

There was a prevalence of girls (62.9%) in this casuistry, perhaps because they are more frequently taken to a doctor (Table 2). The data in the literature do not indicate any predominance of the disease on the basis of gender.¹⁰

In this research two monozygotic twins being studied concomitantly had almost identical lesions in terms of location and size. This phenomenon, although already described,^11-13 is extremely rare. In spite of the different treatments (one used BD, and other a placebo), they both coursed with total repilation and within the same period. Also observed at that time were two other cases of siblings with AA who were not twins, however these had different characteristics. Although genetic factors influence the onset of AA, the exact origin of the defect is unknown.

Patients with atopy develop AA more frequently in childhood, a fact that probably explains the percentile of atopy in this sampling (Table 3). The prevalence of atopy in the general population varies with the criteria used, reaching as much as 23% .¹⁴ It is estimated that in those with AA that value is higher, with ratios varying from 36.8% to 52.4%^15,16 or even of up to 82.1%.¹⁷

The predominant clinical type was AA in plaques (85.7%) (Table 4); Some authors suggest that the most serious forms of AA (total and universalis) occur more frequently among children, citing percentages of 50% (in plaques), 30% (AT), 20% (AU).⁸ In one retrospective study¹⁸ a prevalence of 7% was observed (AU and AT) and the numbers in previous series were questioned, since they could be reflecting extensions of prolonged situations that were observed at a given moment.

The prognosis of AA⁸ is arrived at during the period of follow-up;¹⁷ cases of the disease in localized form can in the future present new and more extensive episodes: 50% of the cases that initiated before puberty and 23% of the cases that initiated after puberty can develop AT. This fact perhaps explains the concentration of cases of AA in plaques in this study, since a more prolonged follow-up would be necessary for the observation of possible recurrences.

The percentiles of response were similar in both therapies: BD (82.3%) and placebo (88.8%) (p = 0.47) (Table 5). In a study on therapeutic response in 119 patients (AA in plaques), a statistically significant difference was not found between minoxidil and a placebo, with total repilation in 60% of the cases with a placebo¹⁹ (Figures 1,2,3 and 4).

The high level of repilation in the sample as a whole (85.7%) (Table 5) is significant because the patients studied were children, to which age group a less favorable course of AA is currently attributed and presents a high rate of recurrence. On the other hand, 20% of the 140 children observed in a five-year study had only a single episode of AA.¹ In view of the short follow-up in this work it was not possible to corroborate that evaluation.

It was also not possible to establish whether the high rate of repilation observed was due to "placebo effect" or to a spontaneous regression of the disease.

The duration of AA before the beginning of the treatment is an important factor in therapeutic response.⁴ It was found that patients less than a year into the development of the disease could expect 100% success in the treatment, while for those with more than eight years a therapeutic failure in 100%. It has been observed that in the interval between eighteen months and eight years therapeutic success is in inverse proportion to the duration of the disease. In this study, the duration of the development of the disease did not influence the therapeutic response (p= 0.99) (Table 6). The disparity of these findings in relation to the literature can be explained by the fact that the disease duration in this sample had an average of only 8.2 months and a maximum duration of 36 months.

Although some authors consider atopy as a part of the criteria for weakened therapeutic response, no statistically significant relationship was observed in our sample between response to treatment and atopic state 20 (p=0.30 and p=0.19) (Tables 7 and 8).

There was no significant difference in the distribution of the clinical type of AA between the two kinds of therapy, which denotes homogeneity of the groups (p=0.35) (Table 9). A tendency was observed to associate positive clinical results with AA in plaques (p = 0.06 close to 0.05) (Table 10). AA in plaques is pointed to having a more favorable course.^4,21,22

Various topical corticosteroids have been tried with success on AA, however only two authors performed controlled double-blind studies.^4,20 One of these evaluated 0.2% fluocinolone acetate in cream under a covering (28 patients) and obtained a response that varied from satisfactory to excellent in 61% of the cases, mainly in children and in cases of shorter duration. The other compared the effects of BD in cream with a placebo, 5% minoxidil and a compound of 5% minoxidil and BD, obtaining repilation rates of 55% with BD and 33% with the placebo. The conclusion was that BD in cream applied twice a day without covering, produces excellent results especially in children, even for those with complete loss of hair.⁵

Even so, cosmetically adequate repilation takes months (minimum of three) to take place, while new hair loss can occur in spite of maintenance therapy.⁵ In working with this group these observations were confirmed. In studies with BD, side effects were localized and not serious, clearing quickly with local hygiene.¹⁰ Three (17.6%) of the 17 patients that used BD presented folliculitis as the only form of complication.

CONCLUSION

- There was no difference between betamethasone dipropionate and the placebo in the treatment of alopecia areata.

- Atopic condition did not influence the therapeutic response.

- Relatives of children with AA present at the consultation dismayed and poorly oriented regarding the diagnosis, treatment and prognosis of the disease.

- There are major difficulties in dealing with a disease whose etiology and clinical course are not well understood.

REFERENCES

• 1. Müller SA, Winkelmann RK. Alopecia Areata - an evaluation of 736 patients. Arch Dermatol 1963; 88: 290-97.
• 2. Ikeda T. A new classification of alopecia areata. Dermatologica 1965; 113: 421-45.
• 3. Dillaha CJ, Rothman S. Treatment of alopecia areata totalis and universalis with cortisone acetate. J. Invest Dermatol 1952; 18: 5-6.
• 4. Pascher F, Kurtin S, Andrade R. Assay of 0,2% fluocinolone acetonide cream for alopecia areata and totalis. Dermatologica 1970; 141: 193-202.
• 5. Fiedler VC. Alopecia areata. A review of therapy, efficacy, safety and mechanism. Arch Dermatol 1992;128: 1519-29.
• 6. Leung DYM. Atopic dermatitis: The skin as a window into the pathogenesis of chronic allergic diseases. J Allergy Clin Immunol 1995; 96 (3): 302-18.
• 7. Hulley SB, Cummings SR. Designing clinical research - An epidemiologic approach. Baltimore: Ed Williams & Wilkins, 1988: 216-17.
• 8. Shellow WVR, Edwards JE, Koo JYM. Profile of alopecia areata: a questionnaire analysis of patient and family. Int J Dermatol 1992;31 (3):186-89.
• 9. De Waard-Van der Spek FB, Orange AP, De Raeymaecker DMJ, Peereboom-Wynia JDR. Juvenile versus maturity-onset alopecia areata - a comparative retrospective clinical study. Clin Exp Dermatol 1989; 14: 429-33.
• 10. Price VH. Alopecia areata: clinical aspects. J Invest Dermatol 1991;96: 68S.
• 11. Hendren OS. Identical alopecia areata in identical twins. Arch Dermat & Syph 1949; 60:793-95.
• 12. Weidman AI, Zion LS, Mamelok AE. Alopecia areata occurring simultaneously in identical twins. Arch Dermatol 1956; 74: 424-26.
• 13. Scerri L, Pace JL. Identical twins with identical alopecia areata. J Am Acad Dermatol 1992;27 (5): 766-67.
• 14. Rothe MJ, Grant-Kels JM. Atopic dermatitis: An update. J Am Acad Dermatol 1996; 35: 1-13.
• 15. Penders AJM. Alopecia areata and atopy. Dermatologica 1968;136: 395-99.
• 16. Young E, Bruns HM, Berrens L. Alopecia areata and atopy. Dermatologica 1978; 156: 306-8.
• 17. Orecchia G, Malagoli P, Santagostino L. Treatment of severe alopecia areata with squaric acid dibutylester in pediatric patients. Pediatr Dermatol 1994; 11 (1):65-8.
• 18. Walker AS, Rothman S. Alopecia areata - a statistical study and consideration of endocrine influences. J Invest Dermatol 1950; 14: 403-13.
• 19. Safavi KH, Muller SA, Suman VJ, Moshell AN. Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc 1995; 70: 628 - 33.
• 20. Fiedler VC, Wendrow A, Szpunar GJ. Treatment-resistant alopecia areata - response to combination therapy with minoxidil plus anthralin. Arch Dermatol, 1990; 126: 756-9.
• 21. Tosti A, Morelli R, Bardazzi F, Peluso AM. Prevalence of nail abnormalities in children with alopecia areata. Pediatric Dermatology 1994; 11 (2) 112-5.
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Correspondence to

Nurimar Conceição Fernandes

Rua Alexandre de Gusmão, 28 - Apto. 201

Rio de Janeiro RJ 20520-120

Tel./Fax: [phone]

Received in October, 11^th of 2001.

Approved by the Consultive Council and accepted for publication in October, 09^th of 2002.

*

Work done at the Instituto de Puericultura e Pediatria Martagão Gesteira - UFRJ e Hospital Municipal Jesus - RJ.

Publication Dates

• Publication in this collection
  01 Nov 2005
• Date of issue
  Feb 2003

History

• Accepted
  09 Oct 2002
• Received
  11 Oct 2001