British Journal of Dermatology (1992) 127, 625-629,
Therapy of alopecia areata with diphencyprone E,HOTING AND A,BOEHM Department of Dermatology, University Clinic Hamburg-Eppendorf. Hamburg, Germany Accepted for publication 1 July 1992
Summary
The properties of diphencyprone (DPC), its possible mechanism of action in the therapy of alopecia areata (AA), and its side-effects are summarized. The results of our own study of treatment in 45 patients with AA, with a mean treatment duration of 72 (15-146) weeks, are presented, and compared with the results of previous studies. We suggest that, in future, therapy protocols should define entry criteria and therapy results more precisely, and include follow-up assessments to establish the length of remission. In view of the low response rates and short lengths of remission, the indications for DPC therapy should be set more rigorously.
The results of numerous investigations in recent years confirm the belief that autoimmune mechanisms are involved in the pathogenesis of AA,'"^ Contact sensitizers, which are thought to act as immunomodulators in A A, have gained in popularity for the treatment of this disorder. Since the early 1980s diphencyprone (DPC) has been the preferred contact sensitizer for topical therapy of AA,'"'' The eliciting of an allergic reaction after application of DPC appears to be an integral part of successful therapy,* Unwanted side-effects include a vesicular contact dermatitis, a generalized eczema, pigmentary changes, and nuchal lymphadenitis,'"" In comparison with other contact sensitizers, DPC does not have the disadvantages of the instability in solution of squaric acid dibutylester (SADBE), or the mutagenic properties of dinitrochlorobenzene (DNCB),''^ However, mutagenic properties of a precursor of DPC and photomutagenic properties of DPC itself have recently been demonstrated,^^ To date, there are no reliable data available about the chronic toxicity and toxicokinetics of DPC, In view of the necessary reaction accompanying therapy, the possible side-effects, and uncertainty about long-term toxicology, indications for DPC therapy should be clearly defined, A necessary prerequisite for the continued use of DPC in the treatment of AA is an assessment of its effectiveness, i,e, the expected mean response rate and length of remission. To this end, we evaluated DPC therapy in 45 patients and compared our results with those of other authors.
Correspondence; Dr E.Hoting, Univ. Hautklinik-Eppendorf, Martinistr. 52, D-2000 Hamburg 20, Germany.
Methods Subjects
The mean age of the patients (n = 45; 21 male, 24 female) at the beginning of therapy was 32 (14-57) years. The presence of alopecia totalis or universalis, or the extension of AA over more than 75% of the scalp, without evidence of spontaneous remission, were prerequisites for the initiation of therapy. If the eyebrows were also affected, they were not treated, because of the risk of causing an allergic blepharoconjunctivitis by spread of DPC into the eyes,^* Children, pregnant women and nursing mothers were excluded. Details elicited in the case history included the duration and course of the disease, and associated disorders such as atopy, vitiligo, and other autoimmune diseases. Regimen
All patients were informed of the nature of the treatment and possible side-effects, and the uncertain long-term toxicology of DPC, and written consent was obtained. The patients were not allowed to administer their own treatment. Following initial sensitization with a 2% DPC solution, DPC was applied once a week to one side only, until hair regrowth on the treated side was clearly recognizable. In this way, it was possible to distinguish spontaneous remission, in which growth over the entire scalp would be expected. The concentration of the solution was increased or reduced depending on the sideeffects, DPC dissolved in acetone was used in the following concentrations: 0-0001, 0-001, 0-01, 0-1, 0-25,0-5,1,1-5, 2 and3%,Ifthere was no response, the treatment was discontinued after 20 applications. When 625
626
E.HOTING AND A.BOEHM
vellus hair regrew within this time period, the treatment was continued, but the regrowth of vellus hair alone was classified as a failure to respond to therapy. Regrowth of pigmented or non-pigmented terminal hair was judged to be a partial remission (PR) if it was necessary to wear a wig because of inadequate density, or gaps in the hair. Complete regrowth, with the exception of a single large bald patch which could be covered by adjacent long hair, was also scored as partial remission. According to our standards, a complete remission (CR) was present when
Table 1, Results of DPC therapy in patients with AA
Patient data No. of patients M/F Age at beginning of therapy (years) (range) Age at first manifestation < 15 years Total duration of disease (years) (range) Duration of therapy (weeks) (range)
x=9 4 (0-1-52) x=72 (14-176)
Form of alopecia Universalis Totaiis Opbiasis Large focus AA (>75%)
n = 20(44%) n = 7 (15%) n = 4 (9%)
Family history Atopy Atopic dermatitis Alopecia areata
n = 9 (20%) n = ] (2%) 1 = 2 (4%)
n = 45 21/24 (14-57)
x=17
Associated diseases Atopy Atopic dermatitis Vitiligo Goitre Response rate Complete remission Partial remission Relapse rate (total) Relapse during therapy No response Side-effects Severe dermatitis Spreading of foci Hyperpigmentation Lymph node swelling
" = 9 (20%) 1 = 4 (9%) 1 = 2 (4%) 1 = 2 (4%) 1 = 9 (20%) 1 = 14(31%) 1 = 15(33%) 1 = 8 (18%) fi = 22(49%) 1 = 20(44%) 1 = 3 (7%) 1 = 1 (2%)
n=14(31%)
all hair regrew, or at the most only two/three bald patches of no more than 1-2 cm in diameter remained, making the wearing of a wig unnecessary.
Results Fourteen of the 45 patients had alopecia universalis, 20 alopecia totaiis, and 11 had alopecia of the ophiasis type, or a multicentric. large focus AA (Table 1). In 17 of the patients with alopecia totaiis, multicentric AA or ophiasis, eyebrows, eyelashes and beard hair were also affected. The first manifestation occurred at an age of less than 15 years in a total of 17 patients. The total duration of the disease prior to starting DPC therapy averaged 9-4 ( 0 1 - 5 2 ) years. Half the patients had experienced an episode of disease activity during the year preceding therapy, A concomitant atopic diathesis was present in 18 (40%) patients, and four (9%) had manifest atopic dermatitis. The family histories suggested a possible atopic diathesis in 10 (22%) of the cases. In two (4%) of the patients the parents or grandparents had suffered from AA, Vitiligo was present in two (4%) of the patients and a euthyroid goitre in two (4%) of the cases (Table 1), The mean duration of therapy was 72 (14-146) weeks. The total observation period, including follow-up examination for which 21 patients attended, averaged 2 - 6 years ( = 136 weeks). The first regrowth of hair appeared on average 17 (432) weeks after the start of treatment. Altogether 23 (51%) patients responded to therapy; nine (20%) obtained a CR and 14 (31%) a PR. Of the nine patients with a CR. four suffered a relapse during therapy and five a relapse after the end of therapy. The length of remission after stopping treatment was 1-24 months ( 2 x 1 , 1 x 5 . 1 X 12.1 X 24 months). In four patients it was possible to maintain a PR after a relapse had occurred by continuation of therapy. Likewise, of the 14 patients with a PR. four suffered a relapse during therapy, and six after stopping therapy. The length of remission varied from 3 months to 5 years ( 1 x 1 , 1 x 3 , 1 x 6 months. 1 x 1 , 1 x 4 , 1 x 5 years). Four patients defaulted without explanation (Table 1). Twenty-two (49%) patients in whom no hair growth was apparent, or only thin, non-pigmented vellus hair regrew, were counted as failing to respond to therapy. Thirteen non-responders were from the group of patients with alopecia universalis (n=14). Of the 18 patients with a total disease duration exceeding 10 years, five responded to therapy (5xPR), whereas of the 17 patients with a short disease duration ( < 1 year). 10 responded to therapy (5 x CR. 5 x PR) [Table 1],
THERAPY OF AA WITH DIPHENCYPRONE
627
Table 2, Survey of results of DPC therapy
Reference
No. of patients
Form of alopecia
Length of therapy Response CR + PR (weeks) rate (%)
Kietzmann et al,. 1985'^
20
Ochsendorf et al,. 1987"
27
Happie et ai. 1984""
34
25 totaiis 9 extensive AA
16-68
Orrecchia, Rabbiosi 1985"
26
10 universalis 7 totaiis 9 patchy AA
16-60
MacDonald-HuU, Norris 1984"
28
13 totaiis n AA > 50-75% 4 AA < 50%
32
Monk, Williams 1988"
15
13 totaiis 2 patchy AA
Ashworth et al. 1989'^
17
9 universalis 8 totaiis
Hoting and Boehm (present study)
45
14 universalis 20 totaiis 11 AA > 7 5 %
7 universalis 1 totaiis 12 AA>25% 1 8 8 8
universalis totaiis AA > 75% AA < 50%
20
20-.'
12 CR 5 PR 10 CR 11 PR
Relapse rate
85
p
77
10 during therapy
70
p
1 CR 13 PR
53
4 during therapy
8CR 4 PR
42
p
52
6 PR
40
10 during therapy
20-30
1 CR 2 PR
17
p
51
19 total. 8 during therapy
14-146
9 CR 14 PR
CR, complete remission; PR, partial remission.
Discussion While Ashworth etal,^^ noted hair regrowth in only 17% of patients. Monk and Williams^' reported 40%, Happie et a/,'* 70% and Kietzmann et aV 85% regrowth (Table 2), Our own response rate was 51%, How can such differences be explained when the substance is applied using identical methodology.' 1. Entrij criteria
The response rate is markedly influenced by the criteria for entry into therapy, Prognostically unfavourable features in the long-term are extensive involvement, disease of long duration and the presence of an atopic diathesis, atopic eczema, or associated autoimmune diseases, A study should therefore always contain an exact description of the patient group, and a definition of the entry criteria. None of the studies listed in Table 2 completely fulfilled these requirements. Only the extent of the involved area was stated by all authors. In accordance with the unfavourable prognosis accompanying extensive hair loss. Ashworth et al,^^ obtained a
response rate of only 17% when patients with alopecia totaiis or universalis were treated, in contrast with a response rate of 77% or 85% observed by authors whose patient groups included a large number of subjects with small focus AA,^^-''' When excellent responses to treatment are reported, the suspicion that spontaneous cures may have influenced the results always arises. In view of the favourable prognosis and high spontaneous cure rates in approximately 30% of cases of small focus AA with involvement of less than 40% of the scalp, some therapeutic measures, including topical DPC, may be difficult to justify.
2, Disease duration before initiation of therapy
According to the observations of Happie et al.^^ the duration of the disease is apparently without influence on the success of DPC therapy. However, MacDonald Hull et a/.'^ attributed their markedly lower response rate of 42% to the fact that only patients with a long disease duration (average 19-9 years) were recruited. In
628
E.HOTING AND A.BOEHM
our group only five out of 18 patients with a total disease duration of more than 10 years responded to treatment, in comparison with 10 of 17 patients with a disease duration of less than 1 year, 3, Definition of complete and partial remission
The differing and somewhat inexact definition of the terms CR. PR and failure to respond to therapy contribute to the strongly contrasting results. According to our criteria, a CR was present when the hair had fully regrown, or a maximum of three bald patches, no larger than 1 cm in diameter, remained. Some other authors did not employ similar exact limits,^'^' In contrast with other authors, we considered a partial remission to be present when a single large focus could be covered by the remaining hair, or more than three foci with a diameter larger than 1 cm were present. We scored the regrowth of vellus hair alone as a failure to respond to therapy. In contrast, MacDonald Hull et al.^^ evaluated vellus hair as the weakest form of response. In other studies it is not evident whether, or how, the regrowth of vellus hair was classified. In an appraisal of the value of DPC therapy in the treatment of AA, the duration of remission must be included, in addition to the response rate. Hence, of 23 of our patients who responded to therapy, eight (35%) had already suffered a relapse during treatment, and a further eight (35%) suffered a relapse within the first year after stopping therapy. In some other reports, details concerning the duration of remission are completely absent. In order to assess the value of DPC treatment in AA, a comparison with other treatment methods should be made. In addition to other contact sensitizers such as SADBE and DNCB, treatments for AA include topical and systemic corticosteroids, PUVA therapy, topical cyclosporin. topical minoxidil. and the immunomodulator inosiplex. However, all these therapies either have significant side-effects, or a real benefit is hardly demonIn conclusion, we consider that the indications for DPC therapy should be set more rigorously, in view of the relatively low response rates and short remission times, and because of possible long-term risks (photomutagenesis. uncertain long-term toxicology). Children, pregnant women and nursing mothers should not be treated. Therapy should be limited to patients with extensive forms of AA involving more than 75% of the scalp in whom the disorder is causing a significant degree of suffering. In future, therapy protocols should precisely
define not only entry criteria, but also therapy outcome, and include follow-up examination to assess the length of remission, as has also been proposed by other authors.^-^^ For these reasons, we suggest that DPC therapy should be carried out in specialized centres, in order to further clarify its role in the treatment of alopecia areata.
References 1 Mitchell AJ, Krull EA. Alopecia areata: pathogenesis and treatment. / Am Acad Dermatol 1984: 11: 763-75. 2 Perret C, Wiesner-Menzel L, Happie R. Immunohistochemical analysis of T-cell subsets in the peribulbar and intrabulbar infiltrates ofalopecia areata. Acta Derm Venereol (Stockh) 1984:64: 26-30. 3 Tosti A. Alopecia areata: more on pathogenesis and therapy. Dermatologica 1989: 178: 61-3. 4 Stute J, Hausen BM, Schulz KH. Diphenylcyciopropenone—ein stark wirksames Kontaktallergen. Dermatosen 1981: 29: 12-14. 5 Happie R. Antigenic competition as a therapeutic concept for alopecia areata. Arch Dermatol Res 1980: 267: 109-14. 6 Orecchia G, Capelli E, Martinetti M et al Decreased in vitro lymphocyte stimulation and reduced sensitivity to IL-2 in patients with alopecia areata. Arch Dermatol Res 1988: 280 (Suppl.): 4 7 50. 7 Orecchia G, Marelli MA, Perfetti L, Rabbiosi G. Alopecia areata: more on topical sensitizers. Dermatologica 1990: 180: 57-9. 8 MacDonald Hull S, Cunliffe WJ, Norris JF. Alopecia areata treated with diphencyprone: is an allergic response necessary? Br / Dermatol 1990: 122: 716-7. 9 Hatzis J, Gourgiotou K, Tosca Aetal Vitiligo as a reaction to topical treatment with diphencyprone. Dermatologica 1988: 177: 146-8. 10 Tosti A, Guerra L, Bardazzi F. Contact urticaria during topical immunotherapy. Contact Dermatitis 1989: 2 1 : 196-7. 11 Perret CM, Steijlen PM, Zaun H et al Erythema multiforme-Iike eruptions: a rare side effect of topical immunotherapy with diphenylcyciopropenone. Dermatologica 1990: 180: 5-7. 12 Ashworth J, Tuyp E, MacKie RM. Allergic and irritant contact dermatitis compared in the treatment of alopecia totaiis and universalis. A comparison of the value of topical diphencyprone and tretinoin gel. Br ] Dermatol 1989: 120: 397-401. 13 Wilkerson MG. Connor TH, Henkin J et al Assessment of diphenylcyciopropenone for photochemically induced mutagenicity in the Ames assay. J Am Acad Dermatol 1987: 17: 606-11. 14 Lutz G, Kreysel HW. Die Therapie der Alopecia areata im Augenbrauenbereich mit Diphenylcyclopropenon und ihre moglichen Risiken, H + G 1988: 64: 898-900. 15 Monk B, Williams HC. Topical diphencyprone therapy in alopecia totaiis. Br I Dermatot 1988: 119 (Suppl. 33): 16-17. 16 Happie R, Hausen BM, Wiesner-Menzel L. Behandlung der Alopecia areata mit Diphencyprone. In: Dermatologische Therapie, Erlangen: G. Mahrle and H. Ippen, Perimed Fachbuch-VerlagsgesellschaftmbH, 1984: 222-7. 17 Kietzmann H, Hardung H, Christophers E. Therapie der Alopecia areata mit Diphenylcyclopropenon. Hautarzt 1985: 36: 331-5 (Ger) (Eng Abstr). 18 MacDonald Hull S, Cunliffe WJ, Gowland G. Alopecia areata: Relapse after diphencyprone and risk factors. Br ] Dermatol 1989: 121(Suppl 34): 20. 19 Happie R. Alopecia areata und Alopecia totaiis: Pathogenese und
THERAPY OF AA WITH DIPHENCYPRONE
20
21 22
23 24
topische Iramunotherapie mit Diphencyprone. Therapiewoche 1986; 36:2706-16, Valsecchi R, Cainelli T, Foiadelli L, Rossi A. Topical immunotherapy of alopecia areata. A follow-up study. Acta Derm Venereol (Stockh) 1985: 66: 269-72, Mitchell A], Douglass MC, Topical photochemotherapy for alopecia areata. / Am Acad Dermatol 1985: 12: 644-9. De Prost Y, Teillac D, Paquez F et al Placebo controlled trial of topical cyclosporin in severe alopecia areata. Lancet 1986: ii: 8 0 3 4. Fiedler-Weiss VC, Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata, / Am Acad Dermatol 1987:16: 745-8, Fiedler-Weiss VC, Potential mechanisms of minoxidil-induced hair growth in alopecia areata. / Am Acad Dermatol 1987: 16: 653-6.
629
25 Perret C, Happie R. Treatment of alopecia areata. In: Hair and Hair Diseases (Orfanos CE, Happie R, eds). Berlin: Springer-Verlag, 1990: 578-83. 26 Naldi L, Parazzini F, Cainelli T. Role of topical immunotherapy in the treatment of alopecia areata. / Am Acad Dermatol 1990: 22: 654-6, 27 Ochsendorf FR, Mitrou G, Milbradt R, Therapie der Alopezia areata mit Diphenylcyclopropenon, H+G 1987: 63: 94-100, 28 Orecchia G, Rabbiosi G. Treatment of alopecia areata with diphencyprone, Dermatologica 1985: 171: 193-6. 29 MacDonald Hull S, Norris JF, Diphencyprone in the treatment of long-standing alopecia areata, Br / Dermatol 1988: 119: 367-74,
Therapy of alopecia areata with diphencyprone E,HOTING AND A,BOEHM Department of Dermatology, University Clinic Hamburg-Eppendorf. Hamburg, Germany Accepted for publication 1 July 1992
Summary
The properties of diphencyprone (DPC), its possible mechanism of action in the therapy of alopecia areata (AA), and its side-effects are summarized. The results of our own study of treatment in 45 patients with AA, with a mean treatment duration of 72 (15-146) weeks, are presented, and compared with the results of previous studies. We suggest that, in future, therapy protocols should define entry criteria and therapy results more precisely, and include follow-up assessments to establish the length of remission. In view of the low response rates and short lengths of remission, the indications for DPC therapy should be set more rigorously.
The results of numerous investigations in recent years confirm the belief that autoimmune mechanisms are involved in the pathogenesis of AA,'"^ Contact sensitizers, which are thought to act as immunomodulators in A A, have gained in popularity for the treatment of this disorder. Since the early 1980s diphencyprone (DPC) has been the preferred contact sensitizer for topical therapy of AA,'"'' The eliciting of an allergic reaction after application of DPC appears to be an integral part of successful therapy,* Unwanted side-effects include a vesicular contact dermatitis, a generalized eczema, pigmentary changes, and nuchal lymphadenitis,'"" In comparison with other contact sensitizers, DPC does not have the disadvantages of the instability in solution of squaric acid dibutylester (SADBE), or the mutagenic properties of dinitrochlorobenzene (DNCB),''^ However, mutagenic properties of a precursor of DPC and photomutagenic properties of DPC itself have recently been demonstrated,^^ To date, there are no reliable data available about the chronic toxicity and toxicokinetics of DPC, In view of the necessary reaction accompanying therapy, the possible side-effects, and uncertainty about long-term toxicology, indications for DPC therapy should be clearly defined, A necessary prerequisite for the continued use of DPC in the treatment of AA is an assessment of its effectiveness, i,e, the expected mean response rate and length of remission. To this end, we evaluated DPC therapy in 45 patients and compared our results with those of other authors.
Correspondence; Dr E.Hoting, Univ. Hautklinik-Eppendorf, Martinistr. 52, D-2000 Hamburg 20, Germany.
Methods Subjects
The mean age of the patients (n = 45; 21 male, 24 female) at the beginning of therapy was 32 (14-57) years. The presence of alopecia totalis or universalis, or the extension of AA over more than 75% of the scalp, without evidence of spontaneous remission, were prerequisites for the initiation of therapy. If the eyebrows were also affected, they were not treated, because of the risk of causing an allergic blepharoconjunctivitis by spread of DPC into the eyes,^* Children, pregnant women and nursing mothers were excluded. Details elicited in the case history included the duration and course of the disease, and associated disorders such as atopy, vitiligo, and other autoimmune diseases. Regimen
All patients were informed of the nature of the treatment and possible side-effects, and the uncertain long-term toxicology of DPC, and written consent was obtained. The patients were not allowed to administer their own treatment. Following initial sensitization with a 2% DPC solution, DPC was applied once a week to one side only, until hair regrowth on the treated side was clearly recognizable. In this way, it was possible to distinguish spontaneous remission, in which growth over the entire scalp would be expected. The concentration of the solution was increased or reduced depending on the sideeffects, DPC dissolved in acetone was used in the following concentrations: 0-0001, 0-001, 0-01, 0-1, 0-25,0-5,1,1-5, 2 and3%,Ifthere was no response, the treatment was discontinued after 20 applications. When 625
626
E.HOTING AND A.BOEHM
vellus hair regrew within this time period, the treatment was continued, but the regrowth of vellus hair alone was classified as a failure to respond to therapy. Regrowth of pigmented or non-pigmented terminal hair was judged to be a partial remission (PR) if it was necessary to wear a wig because of inadequate density, or gaps in the hair. Complete regrowth, with the exception of a single large bald patch which could be covered by adjacent long hair, was also scored as partial remission. According to our standards, a complete remission (CR) was present when
Table 1, Results of DPC therapy in patients with AA
Patient data No. of patients M/F Age at beginning of therapy (years) (range) Age at first manifestation < 15 years Total duration of disease (years) (range) Duration of therapy (weeks) (range)
x=9 4 (0-1-52) x=72 (14-176)
Form of alopecia Universalis Totaiis Opbiasis Large focus AA (>75%)
n = 20(44%) n = 7 (15%) n = 4 (9%)
Family history Atopy Atopic dermatitis Alopecia areata
n = 9 (20%) n = ] (2%) 1 = 2 (4%)
n = 45 21/24 (14-57)
x=17
Associated diseases Atopy Atopic dermatitis Vitiligo Goitre Response rate Complete remission Partial remission Relapse rate (total) Relapse during therapy No response Side-effects Severe dermatitis Spreading of foci Hyperpigmentation Lymph node swelling
" = 9 (20%) 1 = 4 (9%) 1 = 2 (4%) 1 = 2 (4%) 1 = 9 (20%) 1 = 14(31%) 1 = 15(33%) 1 = 8 (18%) fi = 22(49%) 1 = 20(44%) 1 = 3 (7%) 1 = 1 (2%)
n=14(31%)
all hair regrew, or at the most only two/three bald patches of no more than 1-2 cm in diameter remained, making the wearing of a wig unnecessary.
Results Fourteen of the 45 patients had alopecia universalis, 20 alopecia totaiis, and 11 had alopecia of the ophiasis type, or a multicentric. large focus AA (Table 1). In 17 of the patients with alopecia totaiis, multicentric AA or ophiasis, eyebrows, eyelashes and beard hair were also affected. The first manifestation occurred at an age of less than 15 years in a total of 17 patients. The total duration of the disease prior to starting DPC therapy averaged 9-4 ( 0 1 - 5 2 ) years. Half the patients had experienced an episode of disease activity during the year preceding therapy, A concomitant atopic diathesis was present in 18 (40%) patients, and four (9%) had manifest atopic dermatitis. The family histories suggested a possible atopic diathesis in 10 (22%) of the cases. In two (4%) of the patients the parents or grandparents had suffered from AA, Vitiligo was present in two (4%) of the patients and a euthyroid goitre in two (4%) of the cases (Table 1), The mean duration of therapy was 72 (14-146) weeks. The total observation period, including follow-up examination for which 21 patients attended, averaged 2 - 6 years ( = 136 weeks). The first regrowth of hair appeared on average 17 (432) weeks after the start of treatment. Altogether 23 (51%) patients responded to therapy; nine (20%) obtained a CR and 14 (31%) a PR. Of the nine patients with a CR. four suffered a relapse during therapy and five a relapse after the end of therapy. The length of remission after stopping treatment was 1-24 months ( 2 x 1 , 1 x 5 . 1 X 12.1 X 24 months). In four patients it was possible to maintain a PR after a relapse had occurred by continuation of therapy. Likewise, of the 14 patients with a PR. four suffered a relapse during therapy, and six after stopping therapy. The length of remission varied from 3 months to 5 years ( 1 x 1 , 1 x 3 , 1 x 6 months. 1 x 1 , 1 x 4 , 1 x 5 years). Four patients defaulted without explanation (Table 1). Twenty-two (49%) patients in whom no hair growth was apparent, or only thin, non-pigmented vellus hair regrew, were counted as failing to respond to therapy. Thirteen non-responders were from the group of patients with alopecia universalis (n=14). Of the 18 patients with a total disease duration exceeding 10 years, five responded to therapy (5xPR), whereas of the 17 patients with a short disease duration ( < 1 year). 10 responded to therapy (5 x CR. 5 x PR) [Table 1],
THERAPY OF AA WITH DIPHENCYPRONE
627
Table 2, Survey of results of DPC therapy
Reference
No. of patients
Form of alopecia
Length of therapy Response CR + PR (weeks) rate (%)
Kietzmann et al,. 1985'^
20
Ochsendorf et al,. 1987"
27
Happie et ai. 1984""
34
25 totaiis 9 extensive AA
16-68
Orrecchia, Rabbiosi 1985"
26
10 universalis 7 totaiis 9 patchy AA
16-60
MacDonald-HuU, Norris 1984"
28
13 totaiis n AA > 50-75% 4 AA < 50%
32
Monk, Williams 1988"
15
13 totaiis 2 patchy AA
Ashworth et al. 1989'^
17
9 universalis 8 totaiis
Hoting and Boehm (present study)
45
14 universalis 20 totaiis 11 AA > 7 5 %
7 universalis 1 totaiis 12 AA>25% 1 8 8 8
universalis totaiis AA > 75% AA < 50%
20
20-.'
12 CR 5 PR 10 CR 11 PR
Relapse rate
85
p
77
10 during therapy
70
p
1 CR 13 PR
53
4 during therapy
8CR 4 PR
42
p
52
6 PR
40
10 during therapy
20-30
1 CR 2 PR
17
p
51
19 total. 8 during therapy
14-146
9 CR 14 PR
CR, complete remission; PR, partial remission.
Discussion While Ashworth etal,^^ noted hair regrowth in only 17% of patients. Monk and Williams^' reported 40%, Happie et a/,'* 70% and Kietzmann et aV 85% regrowth (Table 2), Our own response rate was 51%, How can such differences be explained when the substance is applied using identical methodology.' 1. Entrij criteria
The response rate is markedly influenced by the criteria for entry into therapy, Prognostically unfavourable features in the long-term are extensive involvement, disease of long duration and the presence of an atopic diathesis, atopic eczema, or associated autoimmune diseases, A study should therefore always contain an exact description of the patient group, and a definition of the entry criteria. None of the studies listed in Table 2 completely fulfilled these requirements. Only the extent of the involved area was stated by all authors. In accordance with the unfavourable prognosis accompanying extensive hair loss. Ashworth et al,^^ obtained a
response rate of only 17% when patients with alopecia totaiis or universalis were treated, in contrast with a response rate of 77% or 85% observed by authors whose patient groups included a large number of subjects with small focus AA,^^-''' When excellent responses to treatment are reported, the suspicion that spontaneous cures may have influenced the results always arises. In view of the favourable prognosis and high spontaneous cure rates in approximately 30% of cases of small focus AA with involvement of less than 40% of the scalp, some therapeutic measures, including topical DPC, may be difficult to justify.
2, Disease duration before initiation of therapy
According to the observations of Happie et al.^^ the duration of the disease is apparently without influence on the success of DPC therapy. However, MacDonald Hull et a/.'^ attributed their markedly lower response rate of 42% to the fact that only patients with a long disease duration (average 19-9 years) were recruited. In
628
E.HOTING AND A.BOEHM
our group only five out of 18 patients with a total disease duration of more than 10 years responded to treatment, in comparison with 10 of 17 patients with a disease duration of less than 1 year, 3, Definition of complete and partial remission
The differing and somewhat inexact definition of the terms CR. PR and failure to respond to therapy contribute to the strongly contrasting results. According to our criteria, a CR was present when the hair had fully regrown, or a maximum of three bald patches, no larger than 1 cm in diameter, remained. Some other authors did not employ similar exact limits,^'^' In contrast with other authors, we considered a partial remission to be present when a single large focus could be covered by the remaining hair, or more than three foci with a diameter larger than 1 cm were present. We scored the regrowth of vellus hair alone as a failure to respond to therapy. In contrast, MacDonald Hull et al.^^ evaluated vellus hair as the weakest form of response. In other studies it is not evident whether, or how, the regrowth of vellus hair was classified. In an appraisal of the value of DPC therapy in the treatment of AA, the duration of remission must be included, in addition to the response rate. Hence, of 23 of our patients who responded to therapy, eight (35%) had already suffered a relapse during treatment, and a further eight (35%) suffered a relapse within the first year after stopping therapy. In some other reports, details concerning the duration of remission are completely absent. In order to assess the value of DPC treatment in AA, a comparison with other treatment methods should be made. In addition to other contact sensitizers such as SADBE and DNCB, treatments for AA include topical and systemic corticosteroids, PUVA therapy, topical cyclosporin. topical minoxidil. and the immunomodulator inosiplex. However, all these therapies either have significant side-effects, or a real benefit is hardly demonIn conclusion, we consider that the indications for DPC therapy should be set more rigorously, in view of the relatively low response rates and short remission times, and because of possible long-term risks (photomutagenesis. uncertain long-term toxicology). Children, pregnant women and nursing mothers should not be treated. Therapy should be limited to patients with extensive forms of AA involving more than 75% of the scalp in whom the disorder is causing a significant degree of suffering. In future, therapy protocols should precisely
define not only entry criteria, but also therapy outcome, and include follow-up examination to assess the length of remission, as has also been proposed by other authors.^-^^ For these reasons, we suggest that DPC therapy should be carried out in specialized centres, in order to further clarify its role in the treatment of alopecia areata.
References 1 Mitchell AJ, Krull EA. Alopecia areata: pathogenesis and treatment. / Am Acad Dermatol 1984: 11: 763-75. 2 Perret C, Wiesner-Menzel L, Happie R. Immunohistochemical analysis of T-cell subsets in the peribulbar and intrabulbar infiltrates ofalopecia areata. Acta Derm Venereol (Stockh) 1984:64: 26-30. 3 Tosti A. Alopecia areata: more on pathogenesis and therapy. Dermatologica 1989: 178: 61-3. 4 Stute J, Hausen BM, Schulz KH. Diphenylcyciopropenone—ein stark wirksames Kontaktallergen. Dermatosen 1981: 29: 12-14. 5 Happie R. Antigenic competition as a therapeutic concept for alopecia areata. Arch Dermatol Res 1980: 267: 109-14. 6 Orecchia G, Capelli E, Martinetti M et al Decreased in vitro lymphocyte stimulation and reduced sensitivity to IL-2 in patients with alopecia areata. Arch Dermatol Res 1988: 280 (Suppl.): 4 7 50. 7 Orecchia G, Marelli MA, Perfetti L, Rabbiosi G. Alopecia areata: more on topical sensitizers. Dermatologica 1990: 180: 57-9. 8 MacDonald Hull S, Cunliffe WJ, Norris JF. Alopecia areata treated with diphencyprone: is an allergic response necessary? Br / Dermatol 1990: 122: 716-7. 9 Hatzis J, Gourgiotou K, Tosca Aetal Vitiligo as a reaction to topical treatment with diphencyprone. Dermatologica 1988: 177: 146-8. 10 Tosti A, Guerra L, Bardazzi F. Contact urticaria during topical immunotherapy. Contact Dermatitis 1989: 2 1 : 196-7. 11 Perret CM, Steijlen PM, Zaun H et al Erythema multiforme-Iike eruptions: a rare side effect of topical immunotherapy with diphenylcyciopropenone. Dermatologica 1990: 180: 5-7. 12 Ashworth J, Tuyp E, MacKie RM. Allergic and irritant contact dermatitis compared in the treatment of alopecia totaiis and universalis. A comparison of the value of topical diphencyprone and tretinoin gel. Br ] Dermatol 1989: 120: 397-401. 13 Wilkerson MG. Connor TH, Henkin J et al Assessment of diphenylcyciopropenone for photochemically induced mutagenicity in the Ames assay. J Am Acad Dermatol 1987: 17: 606-11. 14 Lutz G, Kreysel HW. Die Therapie der Alopecia areata im Augenbrauenbereich mit Diphenylcyclopropenon und ihre moglichen Risiken, H + G 1988: 64: 898-900. 15 Monk B, Williams HC. Topical diphencyprone therapy in alopecia totaiis. Br I Dermatot 1988: 119 (Suppl. 33): 16-17. 16 Happie R, Hausen BM, Wiesner-Menzel L. Behandlung der Alopecia areata mit Diphencyprone. In: Dermatologische Therapie, Erlangen: G. Mahrle and H. Ippen, Perimed Fachbuch-VerlagsgesellschaftmbH, 1984: 222-7. 17 Kietzmann H, Hardung H, Christophers E. Therapie der Alopecia areata mit Diphenylcyclopropenon. Hautarzt 1985: 36: 331-5 (Ger) (Eng Abstr). 18 MacDonald Hull S, Cunliffe WJ, Gowland G. Alopecia areata: Relapse after diphencyprone and risk factors. Br ] Dermatol 1989: 121(Suppl 34): 20. 19 Happie R. Alopecia areata und Alopecia totaiis: Pathogenese und
THERAPY OF AA WITH DIPHENCYPRONE
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topische Iramunotherapie mit Diphencyprone. Therapiewoche 1986; 36:2706-16, Valsecchi R, Cainelli T, Foiadelli L, Rossi A. Topical immunotherapy of alopecia areata. A follow-up study. Acta Derm Venereol (Stockh) 1985: 66: 269-72, Mitchell A], Douglass MC, Topical photochemotherapy for alopecia areata. / Am Acad Dermatol 1985: 12: 644-9. De Prost Y, Teillac D, Paquez F et al Placebo controlled trial of topical cyclosporin in severe alopecia areata. Lancet 1986: ii: 8 0 3 4. Fiedler-Weiss VC, Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata, / Am Acad Dermatol 1987:16: 745-8, Fiedler-Weiss VC, Potential mechanisms of minoxidil-induced hair growth in alopecia areata. / Am Acad Dermatol 1987: 16: 653-6.
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25 Perret C, Happie R. Treatment of alopecia areata. In: Hair and Hair Diseases (Orfanos CE, Happie R, eds). Berlin: Springer-Verlag, 1990: 578-83. 26 Naldi L, Parazzini F, Cainelli T. Role of topical immunotherapy in the treatment of alopecia areata. / Am Acad Dermatol 1990: 22: 654-6, 27 Ochsendorf FR, Mitrou G, Milbradt R, Therapie der Alopezia areata mit Diphenylcyclopropenon, H+G 1987: 63: 94-100, 28 Orecchia G, Rabbiosi G. Treatment of alopecia areata with diphencyprone, Dermatologica 1985: 171: 193-6. 29 MacDonald Hull S, Norris JF, Diphencyprone in the treatment of long-standing alopecia areata, Br / Dermatol 1988: 119: 367-74,
