I II
Alopecia totalis: Is treating nonresponder patients useful? Antonella Tosti, MD, Federico Bardazzi, MD, and Liliana Guerra, M D
Bologna, Italy
The purtx~e of this study was to assess the effectiveness of different treatments in patients with alopecia totalis or universalis who did not respond to sensitizing therapies. Twenty-six patients, who had been receiving sensitizing therapy for at least 1 year without any response, were randomly assigned to receive the following treatments: topical 10% eyclosporine in oily solution (eight patients), PUVA (eight patients), and intravenous thymopentin (ten patients). None of them had any acceptable regrowth after at least 6 months of treatment. Our results suggest that other treatments are not useful in patients with 100% hair loss who fail to respond to sensitizing therapies. (J AM ACADDERMATOL1991;24:455-6.) M a n y clinical and laboratory data suggest that alopecia areata is a heterogeneous disease and that only some patients will respond to treatment. 1-4The aim of this study was to verify this hypothesis. For this purpose we decided to assess the effectiveness of different treatments in patients with alopecia totalis or universalis who had previously failed to respond to sensitizing therapies to determine whether this type of patient may respond to other therapies. MATERIAL AND METHODS From January 1984 to December 1987 we treated with sensitizing therapy 114 patients (65 men and 49 women; mean age 24.26 years, range 16 to 71 years) with alopecia totalis or universalis. Squaric acid dibutylester 2% in acetone or diphencyprone 2% in acetone was used for sensitization; after 3 weeks, weekly applications were carried out with dilutions from 0.0001% to 1% according to the patient's response. Twenty-threeof the 114 patients had hair regrowth that was eosmetieaUy acceptable (20.17%). Of the remaining 91 patients, 60 had sparse regrowth without any cosmetic improvement and 31 patients did not experience any regrowth. The results of treatment were evaluated after at least 1 year of therapy. After being untreated for at least 6 months, 26 of the 31 nonresponder patients were assigned to one of the following therapies: topical 10% cyclosporine, photoehemotherapy, or intravenous thymopentin. Eight patients (four men and four women; mean age 28.7 years, range 22 to 48 years) were treated for 9 months with an oily solution
that contained 10% cyclosporine. Approximately 2 ml of the solution was applied to the scalp daily. Cyclosporine blood levels were monitored monthly by radioimmunoassay. Eight patients (five men and three women; mean age 25.2years, range 16 to 32 years) were treated with photochemotherapy (PUVA) three times a week for 9 months. Ten patients (six men and four women; mean age 24.2 years, range 16 to 31 years) were treated with intravenous thymopentin three times a week for 3 weeks, every 3 months, for 9 months. A 1 ml vial of thymopentin (50 mg/ml) was diluted in physiologic saline to 10 ml and this solution was injected intravenously in 10 minutes. Each of the 26 patients was examined every month durhag treatment and 3 months after therapy. RESULTS None of the 26 patients had any cosmetic clinical improvement at the end of the study. Regrowth of terminal hair was not observed, regardless of the therapy used. A scalp biopsy specimen was obtained from 10 of the 26 patients after treatment. A normal density of small, superficially located hair follicles in early anagen or telogen was detected in eight cases. These follicles were surrounded by an infiltrate of mononuclear inflammatory cells. In two patients the specimens showed a reduced number of follicles surrounded by a sparse inflammatory peribulbar infiltration. Fibrotic tracts that replaced lost hair follicles was also noticed. DISCUSSION
From the Department of Dermatology, University of Bologna. Reprint requests: Prof. Antonella Tosti, Clinica Dermatologica dell'Universi~, Via Massarenti 1,40138, Bologna, Italy.
16/1/~615
In the past 10 years, alopccia areata has been the subject of many studies and many different treatments have proved effective.3-8 However, studies 455
journal of the
456
Tosti et aL
that compare the effectiveness of different therapies in alopecia totalis or universalis are still lacking, as is information on the usefulness of transferring nonresponder patients to other treatments. 9 Because previous studies indicated that topical minoxidil is completely ineffective in patients with 100% hair loss,10, l~ therapeutic trials specifically designed to evaluate new treatments on this subset are needed. Our study was designed to test the hypothesis that patients with 100% scalp hair loss who do not obtain hair regrowth with an appropriate therapy are unlikely to respond to a different treatment. Thus we decided to evaluate the effectiveness of a different treatment in a group of nonrespender patients selected from among a large number of patients with alopecia totalis or universalis who had been treated with topical immunotherapy. Three different treatments were selected and their effectiveness in nonresponder patients was compared. Photochemotherapy and thymopentin were chosen because they have been reported to give results comparable to those obtained with sensitizing therapy, t2-15 W e also decided to assess the possible effects of topical cyclosporine as it has recently been reported to induce hair regrowth in alopecia areata. Although the number of patients who obtain positive results from this drug is still unknown, some patients with severe alopecia areata have had hair regrowth after the use of topical or oral cyclosporine.16, 17 Poor drug penetration could account for the controversial results that have been reported.IS, 19 An optimal topical formulation for cyclosporine needs to be established. W e decided to exclude systemic steroids from our study because of serious long-term side effects. Our results confirm the original opinion that transferring nonresponder patients with alopecia totalis or universalis to other therapies is generally useless. Although our results only concern patients treated with sensitizing therapy, it is possible that similar findings would have been obtained with patients who had received other types of treatment. N o obvious clinical, pathologic, or immunologic features seem to characterize nonresponder patients, and analysis of their clinical data only confirms the poor prognosis of childhood alopecia areata. Scalp biopsy specimens revealed a normal number of hair follicles in most of the nonresponder patients. From a practical standpoint, our study reveals that those patients with 100% hair loss who have not responded
American Academy of Dermatology
to previous treatments should not be placed with other patients when clinical trials are performed for the evaluation of new therapeutic agents. Clinical trials should either exclude these patients altogether or evaluate them separately. The random inclusion of these patients in clinical protocols is an obvious source of misleading results and may explain the heterogeneous clinical results reported by different authors with the same therapy in the management of severe alopecia areata. REFERENCES 1. IkedaT. A new classificationof alopecia areata. Dermatologica 1965;131:421-45. 2. Alopcciaareata--an autoimmune disease [Editorial]. Lancet 1984;1:1335-6. 3. Tosti A, De Padova MP, Minghetti G, et al. Therapies versus placebo in the treatment of patchy alopecia areata. J AM ACAD DERMATOL 1986;15:209-10.
4. Whiting DA. The treatment of alopecia areata. Cutis 1987;40:247-9. 5. Happle R. Antigenic competition as a therapeutic concept for alopecia areata. Arch Dermatol Res 1980;267:109-14, 6. Happle R, Hausen BM, Wiesner-Menzel L. Diphencyproue in the treatment of alopecia areata. Acta Derm Venereol (Stookh) 1983;63:49-52. 7. Valsecchi R, Cainclli T, Foiadelli L, et al. Topical immunotherapy of alopeciaarcata: a foUow-upstudy.Acta Derm Vencreol (Stockh) 1986;66:269-72. 8. CaserioRJ. Treatment of alopecia areata with squaric acid dibutylestcr. Arch Dermatol 1987;1.23:1036-41. 9. Tosti A. Alopecia areata: more on pathogencsis and therapy. Dermatologica 1989;178:61-3. 10. Price VH. Topical minoxidil (3%) in extensive alopecia areata, including long-term efficacy.J AM ACADDERMATOE 1987;16:737-44. 11. Price VII. Topical minoxidil in extensiveaIopecia areata, including 3-year foltow-up.Dermatologica 1987;175(suppl 2);36-41. 12. Claudy AL, Gagnaire D. PUVA treatment of alopecia areata. Arch Dermatol 1983;119:975-8. 13. Van der Schaar WW, Sillevis Smitt JH. An evaluation of PUYA-therapy for alopecia areata. Dermatologica 1984;168:250-2. 14. Tosti A, Manuzzi P, GasponiA. Thymopentin in the treatment of severe alopecia areata. Dermatologica 1988; 177:170-4. 15. Orecchia G. Thymopentin in the treatment of alopecia areata. Dermatologica 1989;178:231-2. t 6. Parodi A, Rebora A. Topicalcyclosporinein alopeciaareata. Arch Dermatol 1987;123:165-6. 17. Gupta AK, Ellis CN, Cooper KD, et al. Oral cyclosporine for the treatment of alopecia areata. J AM ACADDERMATOL 1990;22:242-50. 18. De Prost Y, Teillac D, Paquez F, et al. Placebo-controlled trial of topical cyclosporinin severealopecia areata. Lancet 1986;2:803-4. 19. CoulsonIH, Holden CA. Topical cyclosporinAin alopecia totalis: failure of therapeutic effect due to lack of penetration. Br J Dermatol 1989;121(suppl 34):53-4.
Alopecia totalis: Is treating nonresponder patients useful? Antonella Tosti, MD, Federico Bardazzi, MD, and Liliana Guerra, M D
Bologna, Italy
The purtx~e of this study was to assess the effectiveness of different treatments in patients with alopecia totalis or universalis who did not respond to sensitizing therapies. Twenty-six patients, who had been receiving sensitizing therapy for at least 1 year without any response, were randomly assigned to receive the following treatments: topical 10% eyclosporine in oily solution (eight patients), PUVA (eight patients), and intravenous thymopentin (ten patients). None of them had any acceptable regrowth after at least 6 months of treatment. Our results suggest that other treatments are not useful in patients with 100% hair loss who fail to respond to sensitizing therapies. (J AM ACADDERMATOL1991;24:455-6.) M a n y clinical and laboratory data suggest that alopecia areata is a heterogeneous disease and that only some patients will respond to treatment. 1-4The aim of this study was to verify this hypothesis. For this purpose we decided to assess the effectiveness of different treatments in patients with alopecia totalis or universalis who had previously failed to respond to sensitizing therapies to determine whether this type of patient may respond to other therapies. MATERIAL AND METHODS From January 1984 to December 1987 we treated with sensitizing therapy 114 patients (65 men and 49 women; mean age 24.26 years, range 16 to 71 years) with alopecia totalis or universalis. Squaric acid dibutylester 2% in acetone or diphencyprone 2% in acetone was used for sensitization; after 3 weeks, weekly applications were carried out with dilutions from 0.0001% to 1% according to the patient's response. Twenty-threeof the 114 patients had hair regrowth that was eosmetieaUy acceptable (20.17%). Of the remaining 91 patients, 60 had sparse regrowth without any cosmetic improvement and 31 patients did not experience any regrowth. The results of treatment were evaluated after at least 1 year of therapy. After being untreated for at least 6 months, 26 of the 31 nonresponder patients were assigned to one of the following therapies: topical 10% cyclosporine, photoehemotherapy, or intravenous thymopentin. Eight patients (four men and four women; mean age 28.7 years, range 22 to 48 years) were treated for 9 months with an oily solution
that contained 10% cyclosporine. Approximately 2 ml of the solution was applied to the scalp daily. Cyclosporine blood levels were monitored monthly by radioimmunoassay. Eight patients (five men and three women; mean age 25.2years, range 16 to 32 years) were treated with photochemotherapy (PUVA) three times a week for 9 months. Ten patients (six men and four women; mean age 24.2 years, range 16 to 31 years) were treated with intravenous thymopentin three times a week for 3 weeks, every 3 months, for 9 months. A 1 ml vial of thymopentin (50 mg/ml) was diluted in physiologic saline to 10 ml and this solution was injected intravenously in 10 minutes. Each of the 26 patients was examined every month durhag treatment and 3 months after therapy. RESULTS None of the 26 patients had any cosmetic clinical improvement at the end of the study. Regrowth of terminal hair was not observed, regardless of the therapy used. A scalp biopsy specimen was obtained from 10 of the 26 patients after treatment. A normal density of small, superficially located hair follicles in early anagen or telogen was detected in eight cases. These follicles were surrounded by an infiltrate of mononuclear inflammatory cells. In two patients the specimens showed a reduced number of follicles surrounded by a sparse inflammatory peribulbar infiltration. Fibrotic tracts that replaced lost hair follicles was also noticed. DISCUSSION
From the Department of Dermatology, University of Bologna. Reprint requests: Prof. Antonella Tosti, Clinica Dermatologica dell'Universi~, Via Massarenti 1,40138, Bologna, Italy.
16/1/~615
In the past 10 years, alopccia areata has been the subject of many studies and many different treatments have proved effective.3-8 However, studies 455
journal of the
456
Tosti et aL
that compare the effectiveness of different therapies in alopecia totalis or universalis are still lacking, as is information on the usefulness of transferring nonresponder patients to other treatments. 9 Because previous studies indicated that topical minoxidil is completely ineffective in patients with 100% hair loss,10, l~ therapeutic trials specifically designed to evaluate new treatments on this subset are needed. Our study was designed to test the hypothesis that patients with 100% scalp hair loss who do not obtain hair regrowth with an appropriate therapy are unlikely to respond to a different treatment. Thus we decided to evaluate the effectiveness of a different treatment in a group of nonrespender patients selected from among a large number of patients with alopecia totalis or universalis who had been treated with topical immunotherapy. Three different treatments were selected and their effectiveness in nonresponder patients was compared. Photochemotherapy and thymopentin were chosen because they have been reported to give results comparable to those obtained with sensitizing therapy, t2-15 W e also decided to assess the possible effects of topical cyclosporine as it has recently been reported to induce hair regrowth in alopecia areata. Although the number of patients who obtain positive results from this drug is still unknown, some patients with severe alopecia areata have had hair regrowth after the use of topical or oral cyclosporine.16, 17 Poor drug penetration could account for the controversial results that have been reported.IS, 19 An optimal topical formulation for cyclosporine needs to be established. W e decided to exclude systemic steroids from our study because of serious long-term side effects. Our results confirm the original opinion that transferring nonresponder patients with alopecia totalis or universalis to other therapies is generally useless. Although our results only concern patients treated with sensitizing therapy, it is possible that similar findings would have been obtained with patients who had received other types of treatment. N o obvious clinical, pathologic, or immunologic features seem to characterize nonresponder patients, and analysis of their clinical data only confirms the poor prognosis of childhood alopecia areata. Scalp biopsy specimens revealed a normal number of hair follicles in most of the nonresponder patients. From a practical standpoint, our study reveals that those patients with 100% hair loss who have not responded
American Academy of Dermatology
to previous treatments should not be placed with other patients when clinical trials are performed for the evaluation of new therapeutic agents. Clinical trials should either exclude these patients altogether or evaluate them separately. The random inclusion of these patients in clinical protocols is an obvious source of misleading results and may explain the heterogeneous clinical results reported by different authors with the same therapy in the management of severe alopecia areata. REFERENCES 1. IkedaT. A new classificationof alopecia areata. Dermatologica 1965;131:421-45. 2. Alopcciaareata--an autoimmune disease [Editorial]. Lancet 1984;1:1335-6. 3. Tosti A, De Padova MP, Minghetti G, et al. Therapies versus placebo in the treatment of patchy alopecia areata. J AM ACAD DERMATOL 1986;15:209-10.
4. Whiting DA. The treatment of alopecia areata. Cutis 1987;40:247-9. 5. Happle R. Antigenic competition as a therapeutic concept for alopecia areata. Arch Dermatol Res 1980;267:109-14, 6. Happle R, Hausen BM, Wiesner-Menzel L. Diphencyproue in the treatment of alopecia areata. Acta Derm Venereol (Stookh) 1983;63:49-52. 7. Valsecchi R, Cainclli T, Foiadelli L, et al. Topical immunotherapy of alopeciaarcata: a foUow-upstudy.Acta Derm Vencreol (Stockh) 1986;66:269-72. 8. CaserioRJ. Treatment of alopecia areata with squaric acid dibutylestcr. Arch Dermatol 1987;1.23:1036-41. 9. Tosti A. Alopecia areata: more on pathogencsis and therapy. Dermatologica 1989;178:61-3. 10. Price VH. Topical minoxidil (3%) in extensive alopecia areata, including long-term efficacy.J AM ACADDERMATOE 1987;16:737-44. 11. Price VII. Topical minoxidil in extensiveaIopecia areata, including 3-year foltow-up.Dermatologica 1987;175(suppl 2);36-41. 12. Claudy AL, Gagnaire D. PUVA treatment of alopecia areata. Arch Dermatol 1983;119:975-8. 13. Van der Schaar WW, Sillevis Smitt JH. An evaluation of PUYA-therapy for alopecia areata. Dermatologica 1984;168:250-2. 14. Tosti A, Manuzzi P, GasponiA. Thymopentin in the treatment of severe alopecia areata. Dermatologica 1988; 177:170-4. 15. Orecchia G. Thymopentin in the treatment of alopecia areata. Dermatologica 1989;178:231-2. t 6. Parodi A, Rebora A. Topicalcyclosporinein alopeciaareata. Arch Dermatol 1987;123:165-6. 17. Gupta AK, Ellis CN, Cooper KD, et al. Oral cyclosporine for the treatment of alopecia areata. J AM ACADDERMATOL 1990;22:242-50. 18. De Prost Y, Teillac D, Paquez F, et al. Placebo-controlled trial of topical cyclosporinin severealopecia areata. Lancet 1986;2:803-4. 19. CoulsonIH, Holden CA. Topical cyclosporinAin alopecia totalis: failure of therapeutic effect due to lack of penetration. Br J Dermatol 1989;121(suppl 34):53-4.
