Photochemotherapy for severe psoriasis without or in combination with acitretin: A randomized, double-blind comparison study A. Tanew, MD,a A. Guggenbichler, MD,b H. Honigsmann, MD,a J. M. Geiger, MD,c and P. Fritsch, MDb Vienna and Innsbruck Austria, and Basle, Switzerland J
In a randomized, double-blind comparative study 60 patients with severe, widespread psoriasis were treated either with photochemotherapy (PUVA) alone or in combination with acitretin. Forty-eight patients completed the study; oftbese, 25 received placebo combined with PUVA and 23 received acitretin with PUVA. Marked or complete clearing of psoriasis occurred in 80% of the patients (20 of 25) without acitretin and in 96% of the patients (22 of 23) with adjunctive acitretin administration. The mean cumulative UVA dose given to patients in the acitretin-PUVA group was 42% less than that required for patients in the placebo-PUVA group. We conclude that acitretin substantially augments the efficacy of photochemotherapy in the treatment of severe psoriasis. (J AM ACAD DERMATOL 1991;25: 682-4.) Acitretin is the active metabolite of etretinate. Because it is not stored in adipose tissues, its elimination half-life (55 hours) is strikingly shorter than that of its lipophilic parental drug (100 days) and is comparable to that of 13-cis-retinoic acid. 1-3 Acitretin is as effective as etretinate in the treatment of psoriasis and other disorders of keratinization. In most studies, acitretin was used as monotherapy,4-9 whereas only sparse information is available on its use in combination with oral or topical photochemotherapy (RePl!VA).lO, II We conducted a randomized double-blind study that compared acitretinPUVA with placebo-PUVA in 60 patients with severe widespread psoriasis. We intended to provide additional evidence for the synergistic effect of retinoids and photochemotherapy. This effect has been strongly supported by several open studies, 12·16 but placebo-controlled studies have so far yielded only controversial data. lO, 11, 17
From the Division of Photobiology, Department of Dermatology I, UniveTllity of Vienna,"; the Department of Dermatology, University of Innsbruck,b; and the Department of Clinical Research Dermatology, F. Hoffmann-La Roche & Co. Ltd., Basle.c Supported by a grant from F. Hoffmann-La Roche & Co. Ltd. Reprint requests: Adrian Tanew, MD, Division of Photobiology, Department of Dermatology I, University of Vienna, Alserstrasse 4, A-1090, Vienna, Austria.
16(1(29823
682
PATIENTS AND METHODS
Sixty patients were recruited (40 patients from the Department of Dermatology I, Vienna, and 20 patients from the Department of Dermatology, Innsbruck). Demographic data are given in Table I. Only patients with severe and extensive psoriasis (involvement ofatleast 20% skin surface) were included and assigned randomly to either the acitretin-PUVA (A-PUVA) or the placeboPUVA (P-PUVA) group (30 patients each). Both groups were comparable with regard to severity and extent of psoriasis except for one patient in the A-PUVA group with psoriatic erythroderma (Table I). Acitretin (l mg/kg body weight/day) or placebo was given for 5 days as a monotherapy. Beginning on day 6, photochemotherapy (four PUVA exposures per week) was added to the drug treatment. The combined treatment was continued until complete clearing occurred or for a maximum of 11 weeks. All patients were seen twice weekly by the same investigator for assessment of treatment response and UVA dose adjustments. Photochemotherapy was performed according to the standard European protocol. I8 8-Methoxypsoralen was administered orally as a liquid preparation in soft gelatin capsules (Oxsoralen, GerotPharmazeutika, Vienna, Austria) in a dosage of0.6 mg/kg body weight 1 hour before UVA exposure. For the irradiation a Waldmann PUVA 6000 or a Waldmann PUVA 8001 unit CR. Waldmann, Werk fUr Lichttechnik, Schwenningen, F.R.G.) were used. Informed consent was obtained from all patients. At the end of the study, the duration of treatment, the
Volume 25 Number 4 October 1991
Acitretin-PUVA in psoriasis 683
Table III. Clinical side effects Acitretin (n;: 30)
Table I. Patients' characteristics Sex (male/female) Age (yr) Mean (±SD) Range Weight (kg) Mean (±SD) Range Type of psoriasis Chronic plaque Eruptive guttate Erythrodermic
Acitretin-PUVA
Placebo-PUVA
21/9
21/9
40.4 ± 12.8 18-66
49.3 ± 14.5 24-78
76.3 ± 12.9 42-95
74.7 ± 14.2 50-105
28 1 1
28 2
Table II. Treatment duration, number of UVA exposures, and cumulative UVA dose in patients evaluable for efficacy _ _ _ _ _ _ _ _1 Acitretin-PUVA I
Mucous membranes Dry lips/cheilitis Dry nose Dry mouth Conjunctivitis
Skin
Scaling Dry skin Pruritus Hair/nails Hair loss Nail fragility
Data expressed as mean ± standard error of the mean. "Statistically significant difference between acitretin·PUVA and pIacebo-PUVA (p < 0.05).
total number of exposures, and the cumulative UVAdose were calculated for the A-PUVA and P-PUVA patients. These were compared in both treatment groups by a twoway analysis of variance model with interaction between two factors, treatment and center (significance level of 5%).
RESULTS Of the 60 patients, 48 completed the study and were included in the statistical analysis. In 12 patients (seven in the A-PUVA group and five in the P-PUVA group) treatment was discontinued before the end point of the study. The reasons for premature cessation of therapy in A-PUVA patients were severe muscle pain (one patient), serum triglycerides exceeding 400 mgjdl (two patients), and irregular drug intake (four patients). The five patients in the P-PUVA group discontinued treatment for reasons unrelated to therapy. Complete remission or marked improvement (i.e., at least 90% clearing of psoriasis) was achieved in
(97%) (57%) (50%) (27%)
18 9 9 2
(60%) (30%) (30%) (7%)
28 (93%) 19 (63%) 6 (20%)
15 (50%) 17 (57%) 4 (13%)
9 (30%) 9 (30%)
3 (10%) 6 (20%)
Table IV. Laboratory data
Placebo-PUVA
Treatment duration 40.2 ± 4.6 51.0 ± 4.7 (days) No. of UVA exposures 15.3 ± 1.9 21.4 ± 2.1 * CumulativeUVAdose 58.7 ± 17.9 101.5 ± 15.8* (joules/cm2)
29 17 15 8
Placebo (n = 30)
"n
Increase from normal to abnormal
Acitretin (n = 28)
Triglycerides Cholesterol SGPT SGOT
8 (29%) 5 (18%) 1 (4%) 4 (15%)*
Placebo (n = 23)
2 (9%) 2 (9%)
1 (4%)
2 (9%)
= 26.
96% ofthe patients (22 of 23) in the A-PUVA group and in 80% of those who received P-PUVA (20 of
25). In the A-PUVA group only the patient with erythrodermic psoriasis did not respond satisfactorily. Details oftreatment are given in Table IIfor both groups. A statistically significant difference (p < 0.05) between A-PUVA and P-PUVA patients was found for the number of exposures (15.3 vs 21.4) and total UVA dose (58.7 vs 101.5 joules! cm2 ), which represents a reduction by 29% in the number of exposures and by 42% in total UVA dose. Clinical side effects of acitretin were similar to those reported in previous studies 4- U • 19 and were, in general, well tolerated (Table III). In only one case (a 54-year-old man) therapy had to be discontinued after 6 weeks of acitretin administration because of extreme muscle pain in the left arm. Laboratory data showed an approximate threefold increase in the incidence of elevated serum triglycerides and a twofold increase in the incidence of elevated serum cholesterol levels in patients who received A-PUVA as compared with those who received P-PUVA (Table IV). Abnormal SGOT val-
684 Tanew et al.
ues were detectable in 15% of patients with acitretin and in 9% of patients with placebo. No difference was found for SGPT values. DISCUSSION
This placebo-controlled, double-blind study provides additional information on two issues. Acitretin appears to be as effective as etretinate in the RePUVA treatment of psoriasis. The combination of acitretin with photochemotherapy clearly increased the percentage of patients with complete or marked remission of psoriasis within the study period as compared with the P-PUVA group. In addition, the number of exposures and total UVA dose were significantly lower in the A-PUVA group. This represents a major advantage not only for practical purposes (i.e., shorter treatment periods) but also with respect to the potential risk ofPUVA-induced carcinogenesis. The magnitude of reduction of the total UVA dose with acitretin in our study (42%) is close to that found by Saurat et aL 10 (41 %) in their controlled multicenter study, although these authors used a lower acitretin dose in combination with photochemotherapy. In our study the mean of the total UVA dose was 58.7 joulesjcm2 in the acitretin group and 101.5 joulesjcm2 in the placebo group. In the trial ofSaurat et aL these figures were given only for patients with at least 90% improvement; these were 57.8 joulesjcm2 in the acitretin group and 97.2 joulesjcm2 in the placebo group. 10 Our data also confirm a synergistic effect between retinoids and photochemotherapy, which hitherto had been demonstrated mainly in uncontrolled clinical investigations. 12- 16 REFERENCES 1. Paravicini U, Camenzind M, Gower M, et a1. Multiple dose pharmacokinetics of Ro 10-1670, the main metabolite of etretinate (Tigason). In: Saurat JH, ed. Retinoids: new trends in research and therapy. Basel: Karger, 1985:289-92. 2. Gr~nhoj-Larsen F, Jakobsen P, Gr~nhoj-Larsen C, et a1. Pharmacokinetics of etretin and etretinate during longterm treatment of psoriasis patients. Pharm Tox 1988; 62:159-65.
J oumal of the American Academy of Dermatology
3. Vahlquist A, Rollman O. Clinical pharmacology of 3 generations of retinoids. Dermatologica 1987;175(suppl 1): 20..7. 4. Camenzind M, Geiger JM, Saurat JH. Clinical efficacy of Ro 10-1670, the main metabolite ofTigason. In: SauratJH, ed. Retinoids: new trends in reseach and therapy. Basel: Karger, 1985:305-8. 5. Lassus A, Geiger JM, Nyblom M, et al. Treatment of severe psoriasis with etretin (Ro 10-1670). Br J Dermatol 1987;117:333-41. 6. Kingston TP, Matt LH, Lowe NJ. Etretin therapy for severe psoriasis. Arch DermatoI1987;123:55-8. 7. Madhok R, Muller SA, Dicken CH. Treatment of psoriasis with etretin: a preliminary report. Mayo Clin Proc 1987;62:1084-9. 8. Gollnick H, Bauer R, Brindley C, et al. Acitretin versus etretinatein psoriasis.J AM ACADDERMATOL 1988;19:45868. 9. Olsen EA, Weed WW, Meyer CJ, et al. A double-blind, placebo-controlled trial of acitretin for the treatment of psoriasis. J AM ACAD DERMATOL 1989;21:681-6. 10. Saurat JH, Geiger JM, Amblard P, et al. Randomized double-blind multicenter study comparing acitretin-PUVA, etretinate-PUVA and placebo-PUVA in the treatment of severe psoriasis. Dermatologica 1988;177 :218-24. 11. Lauharanta J, Geiger JM. A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis. Br J Dermatol 1989;121:107-12. 12. Fritsch PO, Honigsmann H, Jaschke E, et al. Augmentation of oral methoxsalen-photochemotherapy with an oral retinoic acid derivative. J Invest DermatoI1978;70:178-82. 13. Orfanos CE, Pullmann H, Sterry W, et al. Retinoid-PUVA (RePUVA): Systemische Kombinations-Behandlung bei Psoriasis. Z Hautkr 1978;53:494-504. 14. Heidbreder G, Christophers E. Therapy of psoriasis with retinoid plus PUVA: clinical and histologic data. Arch Dermatol Res 1979;264:331-7. 15. Lauharanta J, Juvakoski T, Lassus A. A clinical evaluation of the effects of an aromatic retinoid (Tigason), combination of retinoid and PUVA, and PUVA alone in severe psoriasis. Br J DermatolI981;104:325-32. 16. Grupper C, Berretti B. Treatment of psoriasis by oral PUVA therapy combined with aromatic retinoid (Ro 10-9359); Tigason). Dermatologica 1981;162:404-13. 17. Parker S, Coburn P, Lawrence C, et at. A randomized double-blind comparison of PUVA-etretinate and PUVAplacebo in the treatment of chronic plaque psoriasis. Br J DermatoI1984;110:215-20. 18. Henseler T, Honigsmann H, Wolff K, et at. OraI8-methoxypsoralen photochemotherapy of psoriasis. The European PUVA study: a cooperative study among 18 European centres. Lancet 1981;1:853-7. 19. Geiger JM, Czarnetzki BM. Acitretin (Ro 10-1670, etretin): overall evaluation of clinical studies. Dermatologica 1988;176:182-90.
In a randomized, double-blind comparative study 60 patients with severe, widespread psoriasis were treated either with photochemotherapy (PUVA) alone or in combination with acitretin. Forty-eight patients completed the study; oftbese, 25 received placebo combined with PUVA and 23 received acitretin with PUVA. Marked or complete clearing of psoriasis occurred in 80% of the patients (20 of 25) without acitretin and in 96% of the patients (22 of 23) with adjunctive acitretin administration. The mean cumulative UVA dose given to patients in the acitretin-PUVA group was 42% less than that required for patients in the placebo-PUVA group. We conclude that acitretin substantially augments the efficacy of photochemotherapy in the treatment of severe psoriasis. (J AM ACAD DERMATOL 1991;25: 682-4.) Acitretin is the active metabolite of etretinate. Because it is not stored in adipose tissues, its elimination half-life (55 hours) is strikingly shorter than that of its lipophilic parental drug (100 days) and is comparable to that of 13-cis-retinoic acid. 1-3 Acitretin is as effective as etretinate in the treatment of psoriasis and other disorders of keratinization. In most studies, acitretin was used as monotherapy,4-9 whereas only sparse information is available on its use in combination with oral or topical photochemotherapy (RePl!VA).lO, II We conducted a randomized double-blind study that compared acitretinPUVA with placebo-PUVA in 60 patients with severe widespread psoriasis. We intended to provide additional evidence for the synergistic effect of retinoids and photochemotherapy. This effect has been strongly supported by several open studies, 12·16 but placebo-controlled studies have so far yielded only controversial data. lO, 11, 17
From the Division of Photobiology, Department of Dermatology I, UniveTllity of Vienna,"; the Department of Dermatology, University of Innsbruck,b; and the Department of Clinical Research Dermatology, F. Hoffmann-La Roche & Co. Ltd., Basle.c Supported by a grant from F. Hoffmann-La Roche & Co. Ltd. Reprint requests: Adrian Tanew, MD, Division of Photobiology, Department of Dermatology I, University of Vienna, Alserstrasse 4, A-1090, Vienna, Austria.
16(1(29823
682
PATIENTS AND METHODS
Sixty patients were recruited (40 patients from the Department of Dermatology I, Vienna, and 20 patients from the Department of Dermatology, Innsbruck). Demographic data are given in Table I. Only patients with severe and extensive psoriasis (involvement ofatleast 20% skin surface) were included and assigned randomly to either the acitretin-PUVA (A-PUVA) or the placeboPUVA (P-PUVA) group (30 patients each). Both groups were comparable with regard to severity and extent of psoriasis except for one patient in the A-PUVA group with psoriatic erythroderma (Table I). Acitretin (l mg/kg body weight/day) or placebo was given for 5 days as a monotherapy. Beginning on day 6, photochemotherapy (four PUVA exposures per week) was added to the drug treatment. The combined treatment was continued until complete clearing occurred or for a maximum of 11 weeks. All patients were seen twice weekly by the same investigator for assessment of treatment response and UVA dose adjustments. Photochemotherapy was performed according to the standard European protocol. I8 8-Methoxypsoralen was administered orally as a liquid preparation in soft gelatin capsules (Oxsoralen, GerotPharmazeutika, Vienna, Austria) in a dosage of0.6 mg/kg body weight 1 hour before UVA exposure. For the irradiation a Waldmann PUVA 6000 or a Waldmann PUVA 8001 unit CR. Waldmann, Werk fUr Lichttechnik, Schwenningen, F.R.G.) were used. Informed consent was obtained from all patients. At the end of the study, the duration of treatment, the
Volume 25 Number 4 October 1991
Acitretin-PUVA in psoriasis 683
Table III. Clinical side effects Acitretin (n;: 30)
Table I. Patients' characteristics Sex (male/female) Age (yr) Mean (±SD) Range Weight (kg) Mean (±SD) Range Type of psoriasis Chronic plaque Eruptive guttate Erythrodermic
Acitretin-PUVA
Placebo-PUVA
21/9
21/9
40.4 ± 12.8 18-66
49.3 ± 14.5 24-78
76.3 ± 12.9 42-95
74.7 ± 14.2 50-105
28 1 1
28 2
Table II. Treatment duration, number of UVA exposures, and cumulative UVA dose in patients evaluable for efficacy _ _ _ _ _ _ _ _1 Acitretin-PUVA I
Mucous membranes Dry lips/cheilitis Dry nose Dry mouth Conjunctivitis
Skin
Scaling Dry skin Pruritus Hair/nails Hair loss Nail fragility
Data expressed as mean ± standard error of the mean. "Statistically significant difference between acitretin·PUVA and pIacebo-PUVA (p < 0.05).
total number of exposures, and the cumulative UVAdose were calculated for the A-PUVA and P-PUVA patients. These were compared in both treatment groups by a twoway analysis of variance model with interaction between two factors, treatment and center (significance level of 5%).
RESULTS Of the 60 patients, 48 completed the study and were included in the statistical analysis. In 12 patients (seven in the A-PUVA group and five in the P-PUVA group) treatment was discontinued before the end point of the study. The reasons for premature cessation of therapy in A-PUVA patients were severe muscle pain (one patient), serum triglycerides exceeding 400 mgjdl (two patients), and irregular drug intake (four patients). The five patients in the P-PUVA group discontinued treatment for reasons unrelated to therapy. Complete remission or marked improvement (i.e., at least 90% clearing of psoriasis) was achieved in
(97%) (57%) (50%) (27%)
18 9 9 2
(60%) (30%) (30%) (7%)
28 (93%) 19 (63%) 6 (20%)
15 (50%) 17 (57%) 4 (13%)
9 (30%) 9 (30%)
3 (10%) 6 (20%)
Table IV. Laboratory data
Placebo-PUVA
Treatment duration 40.2 ± 4.6 51.0 ± 4.7 (days) No. of UVA exposures 15.3 ± 1.9 21.4 ± 2.1 * CumulativeUVAdose 58.7 ± 17.9 101.5 ± 15.8* (joules/cm2)
29 17 15 8
Placebo (n = 30)
"n
Increase from normal to abnormal
Acitretin (n = 28)
Triglycerides Cholesterol SGPT SGOT
8 (29%) 5 (18%) 1 (4%) 4 (15%)*
Placebo (n = 23)
2 (9%) 2 (9%)
1 (4%)
2 (9%)
= 26.
96% ofthe patients (22 of 23) in the A-PUVA group and in 80% of those who received P-PUVA (20 of
25). In the A-PUVA group only the patient with erythrodermic psoriasis did not respond satisfactorily. Details oftreatment are given in Table IIfor both groups. A statistically significant difference (p < 0.05) between A-PUVA and P-PUVA patients was found for the number of exposures (15.3 vs 21.4) and total UVA dose (58.7 vs 101.5 joules! cm2 ), which represents a reduction by 29% in the number of exposures and by 42% in total UVA dose. Clinical side effects of acitretin were similar to those reported in previous studies 4- U • 19 and were, in general, well tolerated (Table III). In only one case (a 54-year-old man) therapy had to be discontinued after 6 weeks of acitretin administration because of extreme muscle pain in the left arm. Laboratory data showed an approximate threefold increase in the incidence of elevated serum triglycerides and a twofold increase in the incidence of elevated serum cholesterol levels in patients who received A-PUVA as compared with those who received P-PUVA (Table IV). Abnormal SGOT val-
684 Tanew et al.
ues were detectable in 15% of patients with acitretin and in 9% of patients with placebo. No difference was found for SGPT values. DISCUSSION
This placebo-controlled, double-blind study provides additional information on two issues. Acitretin appears to be as effective as etretinate in the RePUVA treatment of psoriasis. The combination of acitretin with photochemotherapy clearly increased the percentage of patients with complete or marked remission of psoriasis within the study period as compared with the P-PUVA group. In addition, the number of exposures and total UVA dose were significantly lower in the A-PUVA group. This represents a major advantage not only for practical purposes (i.e., shorter treatment periods) but also with respect to the potential risk ofPUVA-induced carcinogenesis. The magnitude of reduction of the total UVA dose with acitretin in our study (42%) is close to that found by Saurat et aL 10 (41 %) in their controlled multicenter study, although these authors used a lower acitretin dose in combination with photochemotherapy. In our study the mean of the total UVA dose was 58.7 joulesjcm2 in the acitretin group and 101.5 joulesjcm2 in the placebo group. In the trial ofSaurat et aL these figures were given only for patients with at least 90% improvement; these were 57.8 joulesjcm2 in the acitretin group and 97.2 joulesjcm2 in the placebo group. 10 Our data also confirm a synergistic effect between retinoids and photochemotherapy, which hitherto had been demonstrated mainly in uncontrolled clinical investigations. 12- 16 REFERENCES 1. Paravicini U, Camenzind M, Gower M, et a1. Multiple dose pharmacokinetics of Ro 10-1670, the main metabolite of etretinate (Tigason). In: Saurat JH, ed. Retinoids: new trends in research and therapy. Basel: Karger, 1985:289-92. 2. Gr~nhoj-Larsen F, Jakobsen P, Gr~nhoj-Larsen C, et a1. Pharmacokinetics of etretin and etretinate during longterm treatment of psoriasis patients. Pharm Tox 1988; 62:159-65.
J oumal of the American Academy of Dermatology
3. Vahlquist A, Rollman O. Clinical pharmacology of 3 generations of retinoids. Dermatologica 1987;175(suppl 1): 20..7. 4. Camenzind M, Geiger JM, Saurat JH. Clinical efficacy of Ro 10-1670, the main metabolite ofTigason. In: SauratJH, ed. Retinoids: new trends in reseach and therapy. Basel: Karger, 1985:305-8. 5. Lassus A, Geiger JM, Nyblom M, et al. Treatment of severe psoriasis with etretin (Ro 10-1670). Br J Dermatol 1987;117:333-41. 6. Kingston TP, Matt LH, Lowe NJ. Etretin therapy for severe psoriasis. Arch DermatoI1987;123:55-8. 7. Madhok R, Muller SA, Dicken CH. Treatment of psoriasis with etretin: a preliminary report. Mayo Clin Proc 1987;62:1084-9. 8. Gollnick H, Bauer R, Brindley C, et al. Acitretin versus etretinatein psoriasis.J AM ACADDERMATOL 1988;19:45868. 9. Olsen EA, Weed WW, Meyer CJ, et al. A double-blind, placebo-controlled trial of acitretin for the treatment of psoriasis. J AM ACAD DERMATOL 1989;21:681-6. 10. Saurat JH, Geiger JM, Amblard P, et al. Randomized double-blind multicenter study comparing acitretin-PUVA, etretinate-PUVA and placebo-PUVA in the treatment of severe psoriasis. Dermatologica 1988;177 :218-24. 11. Lauharanta J, Geiger JM. A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis. Br J Dermatol 1989;121:107-12. 12. Fritsch PO, Honigsmann H, Jaschke E, et al. Augmentation of oral methoxsalen-photochemotherapy with an oral retinoic acid derivative. J Invest DermatoI1978;70:178-82. 13. Orfanos CE, Pullmann H, Sterry W, et al. Retinoid-PUVA (RePUVA): Systemische Kombinations-Behandlung bei Psoriasis. Z Hautkr 1978;53:494-504. 14. Heidbreder G, Christophers E. Therapy of psoriasis with retinoid plus PUVA: clinical and histologic data. Arch Dermatol Res 1979;264:331-7. 15. Lauharanta J, Juvakoski T, Lassus A. A clinical evaluation of the effects of an aromatic retinoid (Tigason), combination of retinoid and PUVA, and PUVA alone in severe psoriasis. Br J DermatolI981;104:325-32. 16. Grupper C, Berretti B. Treatment of psoriasis by oral PUVA therapy combined with aromatic retinoid (Ro 10-9359); Tigason). Dermatologica 1981;162:404-13. 17. Parker S, Coburn P, Lawrence C, et at. A randomized double-blind comparison of PUVA-etretinate and PUVAplacebo in the treatment of chronic plaque psoriasis. Br J DermatoI1984;110:215-20. 18. Henseler T, Honigsmann H, Wolff K, et at. OraI8-methoxypsoralen photochemotherapy of psoriasis. The European PUVA study: a cooperative study among 18 European centres. Lancet 1981;1:853-7. 19. Geiger JM, Czarnetzki BM. Acitretin (Ro 10-1670, etretin): overall evaluation of clinical studies. Dermatologica 1988;176:182-90.
