Retinoids differentially regulate the progression of autoimmune diabetes in three preclinical models in mice.

Retinoids have a variety of biological activities, including immunomodulatory action in a number of inflammatory and autoimmune conditions. Considering the pathogenesis of type 1 diabetes mellitus (T1D), in this study we examined the potential role for retinoids, etretinate and all-trans-retinoic acid (ATRA) in preclinical models of human T1D. When administered prophylactically to CBA/H mice made diabetic with multiple low doses of streptozotocin (MLD-STZ), both drugs effectively prevented clinical signs of diabetes. Prevention of T1D was associated with reduced emergence of primed (autoreactive) CD4(+) CD25(+) T cells, but not with the emergence of Foxp3(+) Treg in the peripheral compartments. Moreover, the animals receiving ATRA exhibited reduced Th1/Th17 response and nitric oxide (NO) production in the peripheral lymphoid tissues, thus shifting the balance towards the anti-inflammatory cytokines. In NOD mice with spontaneous form of diabetes, ATRA prophylaxis, starting at a time point immediately before T1D onset, markedly reduced hyperglycemia and incidence of the disease. However, administration of ATRA to NOD mice in which the proportion and function of CD4(+)Foxp3(+) Treg cells was abrogated by cyclophosphamide (CY), failed to permit progression to T1D. These findings suggest that effectiveness of T1D suppression by retinoids depends on the presence of Tregs which down-modulate immunoinflammatory events at the second "check-point" and allow diabetes progression.

Etretinate enhances the susceptibility of human skin squamous cell carcinoma cells to 5-aminolaevulic acid-based photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolaevulinic acid (5-ALA) is a noninvasive and effective treatment for superficial skin cancers. Etretinate, a derivate of vitamin A, with the chemical formula ethyl(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nona-tetraenoate, has been reported to have antitumour effects and to regulate the proliferation and differentiation of skin cancers. OBJECTIVE: In order to develop more efficient PDT, we investigated whether etretinate enhanced the cytotoxic action of ALA-based PDT against human squamous cell carcinoma cell line, HSC-5. METHOD: The in vitro cytotoxicity was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic cells were detected by double-staining with fluorescent annexin V and propidium iodide. Intracellular protoporphyrin IX (PpIX) converted from exogenous ALA was measured by a fluorescence meter. RESULTS: HSC-5 cells pretreated with a nontoxic concentration of etretinate became more susceptible to the cytotoxic action of ALA-based PDT. Etretinate-pretreated cells underwent apoptosis in response to ALA-based PDT. Etretinate pretreatment resulted in enhanced accumulation of ALA-dependent intracellular PpIX. CONCLUSIONS: The results suggest that etretinate enhances the susceptibility of HSC-5 cells to ALA-based PDT via the intracellular increase of ALA-dependent PpIX. Etretinate might be useful for improvement of ALA-based PDT.

Comparison of the in vitro and in vivo effects of retinoids either alone or in combination with cisplatin and 5-fluorouracil on tumor development and metastasis of melanoma.

PURPOSE: Retinoids have previously been reported to inhibit proliferation of melanoma cell lines in vitro. However, the relative antimetastatic efficacy of various retinoids on melanoma in vivo is unknown. Therefore, we investigated the effects of different retinoids on the invasion and metastasis of murine melanoma B16-F10 cells in vitro and in vivo. Based on the findings, the antitumor effects of a selected retinoid either alone or in combination with cisplatin were also investigated in a preclinical mouse melanoma model. METHODS: Cell proliferation and invasion analyses of murine melanoma B16-F10 cells were assessed in the presence of different retinoids, either alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Experimental lung metastasis assay was performed in this study to investigate the antimetastatic efficacy of retinoids. Additionally, a mouse melanoma model was used to assess the antitumor efficacy of a selected retinoid in combination with cisplatin. RESULTS: Retinoids showed significant antiproliferation and anti-invasion effects on murine melanoma B16-F10 cells. Pretreatment with retinoids increased the sensitivity to CDDP but not to 5-FU in in-vitro. Moreover, the number of metastatic colonies formed in the lungs of mice injected intravenously with B16-F10 cells was significantly reduced by injecting the respective retinoid once a day for 10 days. Treatment with a combination of cisplatin and 13-cis-retinoic acid resulted in a significant reduction in primary tumor size and the number of lung metastatic nodules in melanoma-bearing mice. CONCLUSION: These results suggest that retinoids not only exhibit antimetastatic effect, but also enhance the antitumor activity of cisplatin in vivo.

The effects of vitamin A derivative etretinate on the skin of MRL mice.

MRL/Mp-lpr/lpr (MRL/lpr) mice are characterized by the disorder of apoptosis due to defects in Fas antigens and autoimmune symptoms including spontaneous lupus erythematosus (LE)-like skin lesions. MRL/Mp- + / + (MRL/n) mice do not carry the defect of lpr mutation nor do they exhibit skin disorders during the first six months of life. Retinoids are known to inhibit the proliferation of skin fibroblasts, collagen synthesis, modulate immune responses, and apoptosis by Fas ligand upregulation in skin fibroblasts. We examined changes in dermal thickness and appearance of skin disorders in five months old MRL/lpr mice by oral treatment with etretinate, a retinoic acid derivative. Etretinate treated MRL/lpr mice did not have skin lesions or dermatopathological characteristics including an increase in cells infiltrating the dermis. The mean dermal thickness of MRL/lpr and MRL/n mice treated with etretinate decreased significantly and apoptotic cells density in the dermis of MRL/lpr mice with etretinate was significantly higher compared with the control group (P < 0.05) although MRL/lpr mice have a defect within the Fas antigen. We assumed that etretinate reduced dermal thickness, and suppressed the appearance of skin lesions by inducting apoptosis and perhaps regulation of cytokine expression.

Seguimiento del tratamiento con retinoides en niños con trastornos importantes de la queratinización / Follow-up of children with severe disorders of keratinization under retinoid therapy

Fundamento: los retinoides sistémicos son los fármacos de elección en el tratamiento de los trastornos graves de la queratinización. Objetivo: revisar la eficacia y los efectos secundarios del tratamiento con retinoides a largo plazo en niños con trastornos de la queratinización. Métodos: revisión retrospectiva del seguimiento de doce niños (cinco hombres y siete mujeres) con trastornos de la queratinización y tratados con retinoides orales (etretinato y/o acitretín) durante períodos de tiempo variables entre 7 y 68 meses. Resultados: todos los pacientes excepto uno mostraron mejoría de su enfermedad. Los efectos secundarios comunes (queilitis y sequedad cutánea) fueron casi constantes. Se produjeron elevaciones de las transaminasas en cinco pacientes, que se controlaron al pasar el tiempo o reducir la dosis. No se produjeron efectos secundarios óseos directamente atribuibles a la medicación. Conclusiones: los retinoides orales son eficaces y seguros en el manejo a largo plazo de los trastornos de la queratinización en los niños (AU)

In vivo and in vitro influence of etretinate on erythrocyte membrane fluidity.

The molecular mechanisms underlying the action of synthetic retinoids have been studied intensively, but they are not fully understood yet. It is well known that retinoids exert their effects on gene expression via the retinoic acid receptor. Some observations suggest that the main aromatic retinoid etretinate (Tigason) exerts its therapeutic effect in psoriasis also through an action on the cell membrane. In this paper, we present the results of previously unreleased experiments (when Tigason was still in use) concerning the in vivo and in vitro influence of etretinate on erythrocyte membrane fluidity in psoriatic patients. Erythrocytes from healthy subjects and topically treated psoriatics were chosen as control groups. Membrane fluidity was measured by the electron paramagnetic resonance (EPR) spin-labelling technique. Erythrocytes from psoriatic patients had lower membrane fluidity, a lower antioxidant activity and a greater susceptibility to peroxidation than those from healthy subjects. After treatment with etretinate, a significant increase in erythrocyte membrane fluidity and in antioxidant activity as well as a decrease in lipid peroxidation were observed in erythrocytes from patients. Local therapy of psoriatic lesions had no influence on the improvement in membrane fluidity and antioxidant activity of erythrocytes. Incubation of erythrocytes from healthy controls and topically treated psoriatics with etretinate in vitro confirmed its fluidizing effect on erythrocyte membranes. These data may indicate that two mechanisms lead to an increase in erythrocyte membrane fluidity in psoriatic patients treated with Tigason: the first one, indirect, by improvement of the antioxidant defence system and cell protection against lipid peroxidation, and the second one, by a direct fluidizing effect of etretinate on the erythrocyte membrane.

Etretinate augments interferon beta-1b effects on suppressor cells in multiple sclerosis.

BACKGROUND: Interferon beta treatment is only partially effective in multiple sclerosis (MS) suggesting a potential role for adjunctive therapies. Retinoids can augment the clinical efficacy of type 1 interferons in patients with cancer. We reasoned that the same might hold in MS. Interferon beta-1b added to peripheral blood mononuclear cells in vitro partially reverses the CD8 suppressor cell defect of patients with MS. All-trans retinoic acid added to peripheral blood mononuclear cells from untreated patients with MS or from controls potentiates this ability of interferon beta-1b to augment CD8 suppressor cell function in vitro. OBJECTIVE: To determine whether retinoid administration to patients with MS who are being treated with interferon beta-1b augments their CD8 suppressor cell function. SETTING: A university hospital MS clinic. PARTICIPANTS: Patients with MS who were being treated with interferon beta-1b, 14 patients with secondary progressive MS and 3 patients with relapsing remitting MS. RESULTS: Seventeen patients with MS received etretinate treatment for up to 6 months. Planned dosing was 10 mg 3 times daily for the first month, 25 mg twice daily for the second and third months, and 10 mg twice daily thereafter. The 25-mg twice daily dose was not well tolerated and of the 14 patients who remained in the phase 1 clinical trial through month 3 dose reduction to 10 mg thrice daily was required in 1 patient and to 10 mg twice daily in 4 patients. Eleven patients completed the trial. Etretinate treatment significantly augmented suppressor function over baseline values at 1, 3, and 6 months. No meaningful change was noted in disability or quality of life over the course of the phase 1 clinical trial. Neuropsychological testing of completers suggested improvement on selected aspects of verbal memory at 6 months compared with baseline values. CONCLUSIONS: Etretinate treatment at a dose of 10 mg twice or three times daily augments suppressor cell function in patients with MS receiving interferon beta-1b. Higher dose etretinate treatment (25 mg twice daily) is poorly tolerated by patients with MS. Even at 10 mg twice daily adverse experiences involving the mucous membranes and the skin become troublesome for some, but not all, patients. Whether pulse therapy or administration of retinoid restricted to the day of interferon beta dosing will also augment suppressor function, while being better tolerated, remains to be determined.

Intervention studies on cancer.

This paper (and an extensive supplementary report) considers how far cancer/risk factor associations based on epidemiology have been confirmed by evidence from 226 studies involving interventions other than smoking. Many are small, uncontrolled, of unrepresentative populations, concern cancer markers not cancer, and may involve combinations of agents. Many agents suspected of causing cancer are untested by intervention trials. For seven of 16 agents tested (fibre, folic acid, low-fat diet, riboflavin, zinc, vitamin Bs, and vitamin D), the evidence is clearly inadequate to confirm or deny the epidemiology, while the evidence relating to calcium only concerns biomarkers. For other agents, the evidence relating to cancer itself is weak. In studies where cancer is the endpoint, only three effects have been replicated: (a) selenium supplementation and decreased liver cancer incidence, (b) treatment by the retinoid etretinate and reduced bladder tumours in susceptible individuals, and (c) beta-carotene supplementation and increased lung cancer incidence. Studies involving pre-cancerous conditions as the endpoint, which have a number of practical advantages, more frequently report benefits of intervention. Thus, oral pre-cancerous lesions can certainly be reduced by beta-carotene, vitamin A, and other retinoids, and possibly by vitamin E. It also seems that retinoids can reduce pre-cancerous cervix, skin and lung lesions, that vitamin C and the NSAID sulindac can reduce colonic polyps, and that sunscreens can reduce solar keratoses. Our findings clearly show that the great majority of causal relationships suggested by epidemiology have not been validated by intervention trials. This may be partly due to lack of suitable studies of adequate size or duration, or to using single dietary compounds as agents that are by themselves not responsible for the epidemiologically-observed associations between diet and cancer. However, this lack of validation must cause concern in view of the markedly conflicting evidence on beta-carotene and lung cancer between epidemiological and intervention studies. More intervention studies are needed, but in their absence, caution in interpreting epidemiological findings is warranted.

Expression and function of beta 2 integrin CD11B/CD18 on leukocytes from patients with psoriasis.

The expression of beta 2 integrin CD11b on granulocytes and monocytes from patients with psoriasis vulgaris and pustular psoriasis was examined by flow cytometry. The amount of CD11b expressed on both granulocytes and monocytes was greater in 4 patients with pustular psoriasis than in 16 patients with psoriasis vulgaris. Its expression correlated with the development of pustules on the skin. No difference was seen between healthy blood donors and patients with active psoriasis vulgaris. Three patients with pustular psoriasis were followed during retinoid treatment. Granulocytes and monocytes showed a decrease in CD11b expression after administration of retinoids, in parallel with clearing of the skin. The adherence of granulocytes isolated from psoriasis patients was tested on cultured human umbilical vein endothelium. No significant difference in adherence was observed between control cells and cells from patients with active psoriasis vulgaris. These data indicate that the development of microabscesses in the dermis in psoriasis vulgaris is not related to enhanced beta 2 integrin function. The increased CD11b expression found in patients with pustular psoriasis may, however, serve as a triggering factor for pustule formation in pustular psoriasis.

Inhibitory effect of retinoid on esophageal carcinogenesis in rats induced by N-nitroso-N-methylbutylamine in relation to cellular retinoic acid-binding protein.

The inhibitory effect of a synthetic retinoid, ethyl alltrans-9-(4-methoxy-2, 3, 6-trimethyl-phenyl)-3, 7-dimethyl-2, 4, 6, 8-nonatetraenoate (Tigason), on esophageal carcinogenesis in F344 rats induced by N-nitroso-N-methylbutylamine (NMBA) was evaluated. The animals were given NMBA daily in their drinking water for 21 weeks at a concentration of 15 mg per liter ad libitum starting at 8 weeks of age. One week before the beginning of NMBA treatment, the rats were divided randomly into Tigason-fed and -unfed groups. Thirty-five rats were fed a diet supplemented with Tigason at a concentration of 30 mg per kg of diet, and 80 rats were given a basal diet alone. In NMBA-treated rats, multiple papillomas were seen 11 weeks after NMBA treatment and squamous cell carcinoma developed 12 weeks after NMBA; the tumors increased in number thereafter, and the numbers of papillomas and carcinomas were the same at 17 and 21 weeks after NMBA. At 21 weeks after NMBA treatment, the number of papillomas was similar, regardless of the dietary Tigason supplement, however, the number of esophageal squamous cell carcinomas was significantly lower in the Tigason-fed rats than in -unfed animals (p < 0.025). In normal esophageal tissues, a small amount of cellular retinoic acid-binding protein (cRABP) was detected throughout the experimental period, while during carcinogenesis, the levels of cRABP increased continuously until 16 weeks after NMBA; the cRABP level was higher in papillomas than in squamous cell carcinomas. As Tigason specificially blocked the progression of papillomas to carcinomas, it may be a promising candidate chemopreventive agent in esophageal carcinogenesis.

Differential effect of etretinate on proliferation and extracellular matrix metabolism of human dermal fibroblasts from elderly and young individuals in a novel three-dimensional culture.

The effect of etretinate on proliferation and biosynthesis of collagens and glycosaminoglycans (GAGs) were investigated using human dermal fibroblasts in a novel three-dimensional culture supplemented with L-ascorbic acid 2-phosphate. Fibroblasts from two young and two elderly individuals were studied at different concentrations of etretinate, 0.25, 1.0 and 2.5 microg/ml. Collagens (hydroxyproline) and GAGs (disaccharide units) extracted from the cell layer were analyzed and quantified biochemically by high-performance liquid chromatography (HPLC). Etretinate showed no significant effect on fibroblast proliferation either in the monolayer or the three-dimensional culture. Etretinate increased the collagen or GAGs content in the cell layer, which was prominent at etretinate concentrations of 1.0 and 2.5 or 0.25 microg/ml, respectively in fibroblasts from the elderly (P < 0.05). This effect was not seen in dermal fibroblast from the young. These results suggest that etretinate may have the differential effect on collagen and GAG metabolisms depending on the donor age of the cultured fibroblasts.

In vitro effects of retinoids on mitogen-induced peripheral blood leucocyte responses.

The aim of the present study was to investigate the influence of three different retinoids, isotretinoin, etretinate and acitretin, on the mitogenic response of peripheral blood mononuclear cells (PBMCs) to PHA and PMA in vitro. All three retinoids at high concentrations (10(-4)M) significantly inhibited the mitogenic response of PBMCs to these mitogens. At lower concentrations (10(-5) M and 10(-6) M) none of the three retinoids had any effect on PBMC proliferation in response to PHA. Interestingly, isotretinoin and etretinate significantly enhanced the PMA-induced stimulation of proliferation, whereas acitretin at 10(-5) M failed to influence the mitogenic response to PMA but enhanced it at 10(-6) M. The enhancing effects of retinoids on the proliferative response of PMA-stimulated PBMCs were reversed by rapamycin (10 ng/ml), an immunosuppressant known to inhibit the phorbol ester-induced protein kinase C pathway of lymphocyte activation. In conclusion, our study indicates that retinoids directly trigger the PMA-induced protein kinase C pathway of lymphocyte activation in a concentration-dependent manner. This observation could explain the findings of previous studies showing an in vivo immunopotentiating effect of retinoids on certain immune functions.

Retinoids irreversibly inhibit in vitro growth of Epstein-Barr virus-immortalized B lymphocytes.

Natural and synthetic retinoids have proved to be effective in the treatment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCLs), since these cells closely resemble those that give rise to EBV-related lymphoproliferative disorders in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-retinoic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate. The antiproliferative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in these cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achievable plasma levels. Retinoid-treated cells showed a marked downregulation of CD71 and a decreased S-phase compartment with a parallel accumulation in Gzero/ G1 phases. These cell cycle perturbations were associated with the upregulation of p27 Kip1, a nuclear protein that controls entrance and progression through the cell cycle by inhibiting several cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated status. In fact, retinoid-induced modifications of cell morphology, phenotype (downregulation of CD19, HLA-DR, and s-Ig, and increased expression of CD38 and c-Ig), and IgM production were late events, highly heterogeneous, and often slightly relevant, being therefore only partially indicative of a drug-related differentiative process. Moreover, EBV-encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins were inconstantly downregulated by retinoids, indicating that their growth-inhibitory effect is not mediated by a direct modulation of viral latent antigen expression. The strong antiproliferative activity exerted by retinoids in our experimental model indicates that these compounds may represent a useful tool in the medical management of EBV-related lymphoproliferative disorders of immunosuppressed patients.

Production and secretion of platelet-derived growth factor AB by cultured human keratinocytes: regulatory effects of phorbol 12-myristate 13-acetate, etretinate, 1,25-dihydroxyvitamin D3, and several cytokines.

Platelet-derived growth factor (PDGF) is a potent mitogen for several mesenchymal cells and plays an important role in wound repair. Three PDGF isoforms, PDGF-AA, PDGF-BB, and PDGF-AB, have been found to be generated in various tissues. PDGF-AB production by normal human keratinocytes (NHKs), by human squamous cell carcinoma cell line (HSC-1) cells, and by human dermal fibroblasts (HDFs) was studied in the presence of agents which influence cell growth. Both NHKs and HSC-1 cells spontaneously produced and secreted PDGF-AB. NHKs grown in keratinocyte growth medium produced more PDGF-AB than did those grown in keratinocyte basic medium. Phorbol 12-myristate 13-acetate inhibited PDGF-AB production in NHKs but promoted its production in HSC-1 cells. 1,25-dihydroxyvitamin D3 up-regulated PDGF-AB production, whereas etretinate did not. High levels of calcium in the culture medium induced little change in cellular PDGF-AB levels. Prostaglandin E1 slightly inhibited PDGF-AB production, transforming growth factor beta 1 promoted PDGF-AB production and interferon-gamma, interleukin-1 alpha, and tumor necrosis factor-alpha failed to exert any influence at all. Cultured HDFs did not produce any detectable PDGF-AB. These results suggest that keratinocytes are a major source of cutaneous PDGF and that this factor may therefore play an important role in wound repair and in certain proliferative skin diseases.

The effect of topical retinoic acid (Etretinate) on mouse conjunctival Langerhans cells.

Four groups of BALB/c mice were treated locally with different concentrations (0.1-1.0%) of retinoic acid (Etretinate) ointment for a period of one to four weeks. A fifth group was treated with the ointment base only. Ia-positive dendritic cells were identified by an indirect immunofluorescence technique which was confirmed by ADPase staining. Quantitative counts of Langerhans cells were performed for each group. After four weeks, the 0.1 and 0.2% Etretinate-treated conjunctiva showed no significant reduction in Langerhans cell concentration. However, following 0.5 and 1.0% Etretinate treatment for four weeks, the concentration of Langerhans cells was significantly reduced, and the cells showed morphologic changes, consisting mainly of loss of dendritic processes. Between one and two weeks of therapy at these two high concentrations, no significant changes were found. Light microscopy of the conjunctival epithelium showed marked atrophic changes following four weeks of 0.5 and 1.0% Etretinate treatment compared to no changes with 0.1 and 0.2% Etretinate treatment.

Modulation of collagen synthesis and cell proliferation by retinoids in human skin fibroblasts.

The effect of the retinoids, 13-cis-retinoic acid (-RA), etretinate and all-trans-RA on collagen synthesis and cell proliferation of human skin fibroblasts was studied. These compounds all inhibited collagen synthesis at concentrations between 10(-8) and 10(-5) M after 48 h treatments. The inhibitory effect of 13-cis-RA was the most pronounced. Both all-trans-RA and etretinate inhibited DNA synthesis, to 60% and 53% of control value, respectively, at 10(-5) M. In contrast, 13-cis-RA did not show any significant effect on DNA synthesis at the concentrations used. 13-cis-RA appears to be a unique drug showing a pronounced inhibitor effect on collagen synthesis without affecting DNA synthesis and may prove a useful tool for the treatment of fibrotic diseases.

Low-dose short-term cyclosporine versus etretinate in psoriasis: improvement of skin, nail, and joint involvement.

BACKGROUND: High-dose cyclosporine therapy significantly alleviates psoriasis within 2 to 4 weeks but is associated with a high rate of side effects. Reports are conflicting on the frequency and promptness of relapse after discontinuation of cyclosporine therapy. OBJECTIVE: Our purpose was to compare the efficacy and safety of low-dose cyclosporine with that of etretinate and the stability of remission after replacing cyclosporine therapy with topical anthralin during tapering of cyclosporine. METHODS: In a multicenter study 210 patients with moderate to severe chronic plaque-type psoriasis were randomly assigned to treatment with cyclosporine or etretinate. The initial dosages were 2.5 mg/kg/day for cyclosporine and 0.5 mg/kg/day for etretinate, which could be individually adjusted to 5.0 and 0.75 mg/kg/day, respectively. After a treatment phase of 10 weeks (phase 1) patients receiving cyclosporine were again randomly assigned to a group in which cyclosporine was replaced by topical dithranol (anthralin), or to another group in which the drug was tapered during the next 12 weeks (phase 2). All patients treated with etretinate discontinued therapy after 10 weeks and used topical dithranol. RESULTS: Mean Psoriasis Area and Severity Index decreased by 71% in the cyclosporine group and by 47% in the etretinate group during phase 1. After 10 weeks of treatment 47% of the patients treated with cyclosporine and 10% of those treated with etretinate showed a reduction of more than 80% in skin involvement. Sixty-four percent of the cyclosporine group and 48% of the etretinate group did not require an increase in the initial dosage, resulting in a mean daily dose of 3.0 and 0.53 mg/kg, respectively. There was significant alleviation of nail involvement and joint complaints in both groups. In phase 2 the increase in mean Psoriasis Area and Severity Index and the incidence of relapse were significantly higher in patients in whom cyclosporine was discontinued and replaced by dithranol than in patients in whom cyclosporine was tapered or who were pretreated with etretinate. During treatment four patients from the cyclosporine group and three patients of the etretinate group discontinued the study because of side effects. CONCLUSION: Low-dose short-term cyclosporine therapy for psoriasis is, in comparison with etretinate, highly effective and well tolerated. Individually adjusted cyclosporine therapy allows the majority of patients to continue the low dosage of 2.5 mg/kg/day and still achieve a good clinical response. Remission can be better preserved by tapering the drug than by discontinuing treatment abruptly.