Therapy II m
Treatment of lichen planus with acitretin A double-blind, placebo-controlled study in 65 patients Grete Laurberg, MD, a Jean-M. Geiger, MD, b Niels ttjorth, MD, a Per Holm, MSc, Pharm, ~ Klaus Hou-Jensen, MD, e Keld U. Jacobsen, MD, a Aksel Otkjear Nielsen, MD, a Jeanne Pichard, MSc, Pharrn, b Jorgen Serup, MD, a Annelise Sparre-Jorgensen, MD, a Dennis Sorensen, MD, a Kristian Thestrup-Pedersen, MD, a Kristian Thomsen, MD, a Paul Unna, MD, a and Jette Urup, M D a Basel, Switzerland, and
Hvidovre, Copenhagen, Odense, Silkeborg, Herning, Maribo, Aarhus, and Abenra, Denmark Sixty-five patients with lichen planus were included in a multicenter trial of acitretin. At the end of an 8-week placebo-controlled, double-blind phase, a significantly higher number of patients treated with 30 mg/day acitretin (64%) showed remission or marked improvement compared with placebo (13%). Furthermore, during the subsequent 8-week open phase, 83% of previously placebo-treated patients responded favorably to acitretin therapy. Typical retinoid adverse reactions were present in all patients on active drug. Laboratory studies did not show any clinically significant changes. This study shows that aeitretin is an effective and acceptable therapy for severe cases of lichen planus. (J AM ACAD DERMATOL 1991;24: 434-7.) Cutaneous lichen planus responds to orally administered all-trans-retinoic acid, x 13-cis-retinoic acid, 2 etretinate, 3-6 and acitretin. 7 However, all studies of these retinoids have been uncontrolled. This double-blind study was initiated to compare the efficacy of acitretin with placebo in patients with lichen planus with or without involvement of mucous membranes. Acitretin is the main metabolite of etretinate. It has therapeutic activity virtually identical to that of etretinate 7 but is eliminated much faster from the body. 81~
was confirmed by histologic examination of biopsy specimens.12 In case of atypical histology, the patients were reevaluated clinically and accepted for the trial only if a repeated biopsy was confirmatory. Patients with severely impaired renal or hepatic functions or with severe cardiologic or neurologic disease were excluded. Women of childbearing potential were admitted only if they used reliable contraception. The study conformed to the Declaration of Helsinki, Tokyo, and Venice and was approved by the Ethical Committee. Patients were fully informed about the risks of the treatment, and consent had to be obtained before admission to the study.
MATERIAL AND METHODS Patients
Study design
Sixty-five patients with lichen planus were included in this double-blind, multicenter study. Clinical diagnosis
From the Danish Study Group on Aeitretina (G. Lauerberg, Odense; N. Hjorth, Copenhagen; K. U. Jacobin, Silkeborg; A. O. Nielsen, Herning; J. Serup, Copenhagen; A. Sparre-Jorgensen, Odense; D. Sorensen, Maribo; K. Thestrup-Pedersen, Aarhus; K. Thomsen, Copenhagen; P. Unna, Abenra; J. Orup, Silkeborg); International Clinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland and Hvidovre, Denmarkb; and the Department of Pathology, Rigshospitalet, Copenhagen. e Supported by F. Hoffmann-La Roche, Basel, Switzerland. Reprint requests: Grete Laurberg, MD, Vesterbro 99, DK-9000 Aalborg, Denmark.
16/1/207s6 434
Patients were randomly allocated to one of the two treatment groups: placebo or acitretin. For 8 weeks the patients received daily three capsules (10 mg) of acitretin or placebo. The capsules were identical in size and color. This double-blind phase was followed by an open-treatment phase of 8 weeks, during which all patients received acitretin at dosages between 20 and 50 rag/day. Patients were evaluated at the start and at 4-week intervals during the study. The extension of the disease was noted and the intensity of pruritus, papulosis, and erythema was rated according to the following scale: severe, moderate, mild, and absent. At the end of the double-blind phase and of the open phase, efficacy was assessed by the following scale: remission, marked improvement, slight improvement, no change, and worsening.
Volume 24 Number 3 March ! 991
_Acitretin in lichen planus 435
Table I. Study population characteristics
No. of patients Sex ratio (M/F) Age (yr) Median Range Weight (kg) Median Range Duration of lichen planus (yr) Median Range No. of patients with mucous membrane involvement
Table II. Overview of cases evaluated
Treatment group
No. of patients
Placebo ] Acitretin
Placebo Aeitretin group group
33 16/17
32 17/15
53 19-79
44.5 20-80
70 46-90
73 43-95
2.0 0.1-30 13
1.0 0.1-30 12
At each visit adverse reactions were recorded and their intensity rated as mild, moderate, or severe. Complete laboratory examinations were performed before treatment and at weeks 8 and 16. Serum transaminase and lipid levels were additionally checked at weeks 4 and 12. An overall assessment of tolerability was done at the end of the treatment period for all patients.
Statistical analysis The Wilcoxon two-sample test was used to compare age, weight, height, baseline disease criteria, and the investigators' assessment at week 8. The absolute changes of degree of intensity from baseline (difference between the degree of intensity at baseline and that at week 80 were compared in both groups by using the Wilcoxon one-sample test. The incidence of the main adverse events were compared by using the Fisher's exact probability test (twotailed). The level of significance was 5% for all tests. RESULTS Thirty-three men and 32 women took part in the multicenter study between April 1986 and October 1987. Patients' characteristics are given in Table I. Both treatments were comparable with regard to sex distribution, age, weight, and disease criteria. A total of 20 patients withdrew from the study: four during the double-blind phase, nine at the end of the double-blind phase, and seven during the open phase (Table II).
Efficacy During the double-blind phase the lichen planus improved in both treatment groups (Fig. 1). However, at the end of the 8-week treatment, intensity of
1)ouble-blindphase (wk 0-8) Patients who entered this phase Patients who withdrewfrom study Reason: Lack of efficacy Not related to treatment Patients who completedphase Openphase (wk 9-16) Patients not enteringphase Reason: Remission after double-blind phase Lack of efficacy Not related to treatment Patients who withdrewfrom phase Reason: Remission Lack of efficacy Adverse reactions Not related to treatment Patients who completedbpen phase
33
32
1 1 31
0 2 30*
0 1 1
3 0 2
2 1 1 1 24
2 0 0 2 21
*Two additional patients were not included in evaluation of efficacy (assessable in 28 patients) because of irregular drug intake,
pruritus, papulosis, and erythema was significantly lower (/9
Treatment of lichen planus with acitretin A double-blind, placebo-controlled study in 65 patients Grete Laurberg, MD, a Jean-M. Geiger, MD, b Niels ttjorth, MD, a Per Holm, MSc, Pharm, ~ Klaus Hou-Jensen, MD, e Keld U. Jacobsen, MD, a Aksel Otkjear Nielsen, MD, a Jeanne Pichard, MSc, Pharrn, b Jorgen Serup, MD, a Annelise Sparre-Jorgensen, MD, a Dennis Sorensen, MD, a Kristian Thestrup-Pedersen, MD, a Kristian Thomsen, MD, a Paul Unna, MD, a and Jette Urup, M D a Basel, Switzerland, and
Hvidovre, Copenhagen, Odense, Silkeborg, Herning, Maribo, Aarhus, and Abenra, Denmark Sixty-five patients with lichen planus were included in a multicenter trial of acitretin. At the end of an 8-week placebo-controlled, double-blind phase, a significantly higher number of patients treated with 30 mg/day acitretin (64%) showed remission or marked improvement compared with placebo (13%). Furthermore, during the subsequent 8-week open phase, 83% of previously placebo-treated patients responded favorably to acitretin therapy. Typical retinoid adverse reactions were present in all patients on active drug. Laboratory studies did not show any clinically significant changes. This study shows that aeitretin is an effective and acceptable therapy for severe cases of lichen planus. (J AM ACAD DERMATOL 1991;24: 434-7.) Cutaneous lichen planus responds to orally administered all-trans-retinoic acid, x 13-cis-retinoic acid, 2 etretinate, 3-6 and acitretin. 7 However, all studies of these retinoids have been uncontrolled. This double-blind study was initiated to compare the efficacy of acitretin with placebo in patients with lichen planus with or without involvement of mucous membranes. Acitretin is the main metabolite of etretinate. It has therapeutic activity virtually identical to that of etretinate 7 but is eliminated much faster from the body. 81~
was confirmed by histologic examination of biopsy specimens.12 In case of atypical histology, the patients were reevaluated clinically and accepted for the trial only if a repeated biopsy was confirmatory. Patients with severely impaired renal or hepatic functions or with severe cardiologic or neurologic disease were excluded. Women of childbearing potential were admitted only if they used reliable contraception. The study conformed to the Declaration of Helsinki, Tokyo, and Venice and was approved by the Ethical Committee. Patients were fully informed about the risks of the treatment, and consent had to be obtained before admission to the study.
MATERIAL AND METHODS Patients
Study design
Sixty-five patients with lichen planus were included in this double-blind, multicenter study. Clinical diagnosis
From the Danish Study Group on Aeitretina (G. Lauerberg, Odense; N. Hjorth, Copenhagen; K. U. Jacobin, Silkeborg; A. O. Nielsen, Herning; J. Serup, Copenhagen; A. Sparre-Jorgensen, Odense; D. Sorensen, Maribo; K. Thestrup-Pedersen, Aarhus; K. Thomsen, Copenhagen; P. Unna, Abenra; J. Orup, Silkeborg); International Clinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland and Hvidovre, Denmarkb; and the Department of Pathology, Rigshospitalet, Copenhagen. e Supported by F. Hoffmann-La Roche, Basel, Switzerland. Reprint requests: Grete Laurberg, MD, Vesterbro 99, DK-9000 Aalborg, Denmark.
16/1/207s6 434
Patients were randomly allocated to one of the two treatment groups: placebo or acitretin. For 8 weeks the patients received daily three capsules (10 mg) of acitretin or placebo. The capsules were identical in size and color. This double-blind phase was followed by an open-treatment phase of 8 weeks, during which all patients received acitretin at dosages between 20 and 50 rag/day. Patients were evaluated at the start and at 4-week intervals during the study. The extension of the disease was noted and the intensity of pruritus, papulosis, and erythema was rated according to the following scale: severe, moderate, mild, and absent. At the end of the double-blind phase and of the open phase, efficacy was assessed by the following scale: remission, marked improvement, slight improvement, no change, and worsening.
Volume 24 Number 3 March ! 991
_Acitretin in lichen planus 435
Table I. Study population characteristics
No. of patients Sex ratio (M/F) Age (yr) Median Range Weight (kg) Median Range Duration of lichen planus (yr) Median Range No. of patients with mucous membrane involvement
Table II. Overview of cases evaluated
Treatment group
No. of patients
Placebo ] Acitretin
Placebo Aeitretin group group
33 16/17
32 17/15
53 19-79
44.5 20-80
70 46-90
73 43-95
2.0 0.1-30 13
1.0 0.1-30 12
At each visit adverse reactions were recorded and their intensity rated as mild, moderate, or severe. Complete laboratory examinations were performed before treatment and at weeks 8 and 16. Serum transaminase and lipid levels were additionally checked at weeks 4 and 12. An overall assessment of tolerability was done at the end of the treatment period for all patients.
Statistical analysis The Wilcoxon two-sample test was used to compare age, weight, height, baseline disease criteria, and the investigators' assessment at week 8. The absolute changes of degree of intensity from baseline (difference between the degree of intensity at baseline and that at week 80 were compared in both groups by using the Wilcoxon one-sample test. The incidence of the main adverse events were compared by using the Fisher's exact probability test (twotailed). The level of significance was 5% for all tests. RESULTS Thirty-three men and 32 women took part in the multicenter study between April 1986 and October 1987. Patients' characteristics are given in Table I. Both treatments were comparable with regard to sex distribution, age, weight, and disease criteria. A total of 20 patients withdrew from the study: four during the double-blind phase, nine at the end of the double-blind phase, and seven during the open phase (Table II).
Efficacy During the double-blind phase the lichen planus improved in both treatment groups (Fig. 1). However, at the end of the 8-week treatment, intensity of
1)ouble-blindphase (wk 0-8) Patients who entered this phase Patients who withdrewfrom study Reason: Lack of efficacy Not related to treatment Patients who completedphase Openphase (wk 9-16) Patients not enteringphase Reason: Remission after double-blind phase Lack of efficacy Not related to treatment Patients who withdrewfrom phase Reason: Remission Lack of efficacy Adverse reactions Not related to treatment Patients who completedbpen phase
33
32
1 1 31
0 2 30*
0 1 1
3 0 2
2 1 1 1 24
2 0 0 2 21
*Two additional patients were not included in evaluation of efficacy (assessable in 28 patients) because of irregular drug intake,
pruritus, papulosis, and erythema was significantly lower (/9
