Oral treatment of pustulosis palmo-plantaris with a new retinoid, Ro 10-9359.

Ro 10-9359 is a retinoic acid derivative, selected for study because of a better tolerance than retinoic acid, shown in animal experiments. Earlier clinical experience has proved Ro 10-9359 to be an extremely potent antipsoriatic drug. The well-known association between psoriasis and pustulosis palmoplantaris was a motivation to evaluate Ro 10-9359 also in the last-mentioned disease, which is notoriously known to be resistant to treatment. In this study 30 patients were given either 75 mg/day of Ro 10-9359 or 200 mg twice every week according to a randomized pattern. All patients had suffered from the disease for at least 2 years without any spontaneous remission during the year preceding the trial. After a treatment period of about 2 weeks with Ro 10-9359 hyperkeratotic scales had usually disappeared, and 2 weeks later there were in general significantly less pustular lesions. The treatment continued for 8 weeks, and at this time the average reduction of the number of pustules was 80%. The daily dosage seemed to give better results and was also better tolerated than was the twice-weekly dosage. Side effects were common, but generally mild. On average, the remission lasted 1 month after cessation of therapy.     

Systemic treatment of psoriasis with an oral retinoic acid derivative (Ro 10-9359)

Ninety-seven patients with severe psoriasis took part in a 1-year study to evaluate the effect of a new oral synthetic retinoid (Ro 10-9359). The trial was performed in a double-blind cross-over fashion. The treatment started with either 100 mg daily of Ro 10-9359 or placebo and the maintenance dose was in most cases 50 mg. Follow-up examinations were performed monthly and the parameters erythema, desquamation, infiltration and extent of the lesions were followed. Throughout the study there was a significant to highly significant preference for Ro 10-9359 shown by all parameters. More patients were in complete remission after Ro 10-9359 periods than after placebo periods. The side-effects of Ro 10-9359 on uninvolved skin and mucous membranes seemed to be largely dose-dependent. Twenty-three patients interrupted the study, four of them because of side-effects, mainly alopecia. Laboratory examinations revealed no aberrations which could be attributed to the therapy. One patient developed hepatitis during a placebo period.     

Acitretin versus etretinate in psoriasis. Clinical and pharmacokinetic results of a German multicenter study

175 patients with severe psoriasis of different types were treated with 10, 25, or 50 mg acitretin and compared with patients receiving 50 mg etretinate over a period of 8 weeks in a randomized, double-blind multicenter study in the Federal Republic of Germany. Plasma concentrations of etretinate and its metabolite acitretin were measured during therapy and also 3 weeks after cessation of treatment. After 4 weeks of treatment, a trend toward clinical improvement was shown in all groups with increasing dosage. Those groups receiving the lower acitretin doses (i.e., 10 and 25 mg/day) had more dropouts than the groups taking 50 mg acitretin or 50 mg etretinate. Complete remissions before the end of therapy occurred only among those receiving higher doses. Enlargement of psoriatic lesions, however, could be observed during treatment with both retinoids, despite improvement of other parameters, as measured by psoriasis area and severity index (PASI) and psoriasis severity index (PSI). After 8 weeks, a significant improvement was calculated by the PASI score and by a newly defined, corrected PASI score for all four dose regimens compared with baseline levels. A greater than 50% PSI score improvement was seen in 50% of patients treated with 10 mg acitretin, 40.5% with 25 mg acitretin, 53.8% with 50 mg acitretin, and 61.1% with 50 mg etretinate. No statistical differences were found among these groups at any time during the 8-week period. No new or unexpected side effects occurred during acitretin treatment. Moreover, cholesterol levels did not significantly change. Three weeks after cessation of drug administration, the plasma concentrations of acitretin were below the sensitivity level of the assay, whereas etretinate was still quantifiable. It is interesting that acitretin plasma concentrations during therapy with 50 mg acitretin were markedly lower (means = 18 ng/ml) than were acitretin levels during treatment with 50 mg etretinate (means = 36 ng/ml).     

Treatment of congenital erythroderma ichthyosiforme in mother and son with the oral aromatic retinoid Ro 10-9359. The need for maintenance therapy

Aromatic retinoid Ro 10-9359 (Tigason) administered in the doses 25-50 mg daily to two patients (mother and son) suffering from congenital non-bullous ichthyosiform erythroderma revealed complete disappearance of the clinical signs of the disease within two weeks. A relapse was noted in one patient 1.5 months after oral treatment was discontinued. The lesions disappeared again after 30 mg of Ro 10-9359 daily within 10 days. No side-effects were recorded. The tolerance of the drug was satisfactory. The obtained data showed a high efficacy of the oral aromatic retinoid in the therapy of congenital ichthyosiform erythroderma and point to the necessity of maintainance treatment with small daily doses of retinoid for longer time periods.     

Our experience with etanercept in the treatment of psoriasis

Psoriasis is a chronic inflammatory disorder that usually requires long-term control. Etanercept has been shown to be effective in this disease. The efficacy and safety of etanercept were assessed in patients with psoriasis. In this 16-week open clinical trial, 29 patients with clinically stable psoriasis and psoriatic arthritis received etanercept (25 mg twice weekly) subcutaneously. All patients were evaluated for the psoriasis area, severity index (PASI) and Ritchie's articular index (RAI) which measures arthritis disease activity. Improvement by 75 percent in PASI, considered significant for psoriasis remission, was observed in nearly sixty percent of patients after 12-week etanercept therapy. The percentage of PASI improvement was nearly 25% at two weeks, 52.3% at four weeks and 78% at 12 weeks of etanercept treatment, and was maintained for the next four weeks. Comparable results were obtained in the improvement of psoriatic arthritis symptoms, as improvement of 75 percent in RAI was observed in 58.3 percent of patients after 12 weeks of etanercept therapy. The percentage of RAI improvement was nearly 26% at two weeks, 40.5% at four weeks and 73.6% at 12 weeks and 77.1% at 16 weeks of etanercept treatment. Etanercept was generally well tolerated, as most events were of mild severity. The treatment with etanercept led to significant improvement in patients with psoriasis over a period of 16 weeks.     

Ultrastructural evidence suggesting an immunomodulatory activity of oral retinoid

The effects of the aromatic retinoid Ro 10-9359 on the fine structure of psoriatic dermis were investigated by electron microscopy in five patients after 1, 2, and 3 weeks of treatment (1 mg/kg/day). Our findings show that aromatic retinoid, additionally to its epidermal effects, exerts a distinct influence on dermal components in psoriasis. Ultrastructural evidence is provided suggesting that this drug stimulates lymphocytes and monocytes, promoting their differentiation into Sézary-like lymphocytic cells, activated macrophages and dermal Langerhans cells. The appearance of these immunocompetent cell lines may modulate the cell-mediated immune response in psoriasis, obviously reflecting a pharmacological action of the drug additional to its definite influence on epidermal keratinization.     

Oral treatment of keratosis follicularis with a new aromatic retinoid

Four patients with extensive keratosis follicularis (Darler's disease) showed excellent clinical response to the oral administration of a new aromatic derivative of retinoic acid (RO 10-9359). Initial oral treatment with 50 to 75 mg of the drug was followed by substantial improvement in four to seven days and the lesions cleared completely after three to four weeks. Long-term treatment with 25 to 30 mg/day was sufficient to prevent recurrence. No serious side effects were seen with this dosage after several months. Some dryness of the lips and the nasal mucosa occurred and one patient experienced slight nausea. Histological investigations showed the gradual disappearance of acantholysis, dyskeratosis, and hyperkeratosis, in this order. The given therapeutic schedule is a reliable routine management for keratosis follicularis in adults.     

Topical calcipotriol in the treatment of intertriginous psoriasis

Summary The purpose of this study was to examine the effectiveness and side-effects of the vitamin D analogue calcipotriol, applied topically to psoriatic skin lesions in intertriginous areas, in an open and uncontrolled trial. Twelve patients with psoriasis vulgaris who presented with psoriatic lesions in the axilla, and inguinal and anal folds, were treated with calcipotriol ointment (50μg/g) twice daily for 6 weeks. Examination and photographic documentation were performed before treatment, at 3 weeks of treatment, and at 6 weeks of treatment. The mean improvement in the extent and severity of the psoriatic plaques was determined with a semiquantitative grading system closely realted to the psoriasis area and severity index (M-PASI). Two of 12 patients showed insufficient response to therapy. Five of 12 patients showed a quick response within 3 weeks or less, and five of 12 patients showed a slow response which could be seen only after 6 weeks of treatment. Minimal burning was reported in one patient, slight lesional and/or perilesional irritation in five patients, and, in the remaining, no side-effects occurred. Topical calcipotriol is an effective and safe treatment for intertriginous psoriasis.     

Oral tofacitinib efficacy,safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: A randomized,double‐blind,phase 3 study

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double‐blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open‐label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end‐points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physician's Global Assessment of “clear” or “almost clear” (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty‐seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.     

Infliximab efficacy in nail psoriasis. A retrospective study in 48 patients

Background Nail psoriasis occurs in up to half of psoriatic patients and can lead to significant physical impairment and pain. To date, patients and clinicians are actually dissatisfied by current therapeutic approaches. Objective Our main aim is to evaluate Infliximab efficacy in nail psoriasis. Methods We performed an open‐label and uncontrolled retrospective study considering all psoriatic patients presenting recalcitrant nail involvement and receiving Infliximab in our Department during the period between January 2008 and March 2009. We calculated nail psoriasis severity index (NAPSI) score at 0, 14, 22 and 38 weeks and percentage of patients achieving NAPSI‐50,‐75,‐90 at 14, 22 and 38 weeks. Results We observed a rapid nail improvement in most cases after 22 weeks of Infliximab therapy, but a complete nail clearing was reached in only five (10.4%) patients. We don’t have a follow‐up longer than 38 weeks to assess long‐term efficacy of this treatment in nail psoriasis. Conclusions Infliximab, in our experience, has proved to be effective in reducing nail lesions and, in some cases, even clearing them. Our data demonstrate long‐term efficacy of this biological agent in nail psoriasis.     

Efficacy and Safety of Etanercept in Psoriasis after Switching from Other Treatments

Background: Since targeted biologic treatments have been introduced for the treatment of plaque-type psoriasis and psoriatic arthritis, switching between different medications has become necessary in selected patients, particularly after treatment failures. Objective: To evaluate the efficacy and safety of etanercept treatment in adult patients with psoriasis after failure to respond to other previous therapies. In particular, the differences in efficacy profiles after switching from traditional (cyclosporine [ciclosporin], methotrexate, retinoids, fumaric acid esters, psoralen plus UVA therapy, corticosteroids) or biologic (infliximab, efalizumab) treatments were analyzed. Methods: The study included 124 patients affected by plaque-type psoriasis who received etanercept administered subcutaneously at a dosage of 50 mg twice weekly for 12 weeks, followed by 25 mg twice weekly for an additional 12 weeks, and 110 patients affected by psoriatic arthritis who were treated with etanercept 25 mg twice weekly in a continuous regimen, after a 12-week period of treatment with etanercept 50 mg twice weekly. Results: Efficacy results were consistent in both groups of patients (plaque-type psoriasis and psoriatic arthritis), as expressed by the percentage of patients who achieved Psoriasis Area and Severity Index (PASI) 50 and PASI 75 scores. Among psoriatic arthritis patients, the mean pain Visual Analog Scale (VAS) score showed a substantial reduction during the treatment course, from 67.2 at week 0 to 15.8 at week 24. After 24 weeks, among patients with plaque-type psoriasis who had not previously received biologic therapies, 89.9% of patients achieved PASI 50 and 75.3% achieved PASI 75, while among patients who had received biologic therapies, 69.6% of patients achieved PASI 50 and 65.2% achieved PASI 75. In addition, 92.3% of patients with psoriatic arthritis who had not previously received biologic therapies achieved PASI 50 and 73.8% achieved PASI 75, while among patients who had received biologic therapies, 45.8% of patients achieved PASI 50 and 29.2% achieved PASI 75. Conclusions: Our study demonstrated that etanercept was more effective in those patients who had not previously received other biologic therapies than in those who had. The results of the present study indicate that etanercept may represent a valid, effective, and well tolerated therapeutic alternative even after failure to respond to traditional and other biologic therapies.     

银屑病患者血清和皮损中血管内皮细胞粘附分子的对比研究

目的 探讨银屑病患者血清和皮损中4种血管内皮粘附分子表达与银屑病疾病活动性之间的关系。方法 采用ELISA法检测36例银屑病患者治疗前后和36例健康人的血清中可溶性粘附分子（sICAM-1、sICAM-3、sVCAM-1、sELAM）的浓度。同时用ABC免疫组化染色技术检测了36例银屑病患者皮损和临床治愈处皮肤粘附分子（ICAM－1、ICAM－3、VCAM－1、ELAM）的表达情况。结果 与正常人相比，银屑病患者皮损部位4种粘附分子的原位表达呈明显上调（P＜0.005），同时患者血清中4种可溶性粘附分子浓度也明显升高（P＜0.001）。经治疗后银屑病患者皮损部位4种粘附分子的原位表达明显下调（P＜0.05），同时血清中4种可溶性粘附分子浓度比前也下降（P＜0.05）；血清中4种可溶性粘附分子的浓度与银屑病疾病活动严重指数（PASI）均呈正相关，但治疗前后sVCAM-1的水平上升和下降的幅度最大，且与PASI的相关性最好。结论 血管内皮细胞粘附分子参与银屑病的发病机制；患者血清中可溶性粘附分子浓度的升高可能与皮损部位血管内皮细胞上相应的粘附分子高表达有关；血清VCAM－1的水平可以作为反映银屑病疾病活动的一个新的敏感指标。     

维A酸治疗银屑病致维A酸综合征一例

报道维A酸治疗银屑病致维A酸综合征1例。患者男,32岁。有寻常性银屑病病史10余年。患者10余年来,头皮、躯干、四肢反复发红色斑丘疹、斑块,表面覆有多层银白色鳞屑,伴瘙痒,确诊为银屑病,长期口服维生素类、中成药及外用药物治疗,皮损缓解与加重交替。半年前因皮疹加重,给予阿维A（方希）胶囊10 mg每日2次共20 d,后增至10 mg每日3次共30 d,皮疹好转后,减至10 mg每日2次巩固治疗,连续用药半年,皮疹基本消退。就诊前1周改为口服维胺酯（三蕊）胶囊50 mg每日2次,3 d后皮疹加重,炎症反应明显,随后皮疹迅速泛发全身,融合成大片状,水肿明显,大量脱屑,伴高热,体温达39 ℃以上,并伴低血压、呼吸困难、肺水肿、胸腔和心包积液、肾功能异常及血白细胞明显升高。诊断为维A酸综合征。经糖皮质激素及对症支持治疗,症状均改善。维A酸综合征发生急骤,病情凶险,需及时诊断、并积极采用糖皮质激素及对症支持治疗。     

Excessive costimulation of CD3-dependent lymphocyte response by extracellular matrix proteins in severe widespread psoriasis

Costimulation of anti-CD3-triggered proliferative T-cell responses by type I and type IV collagen and fibronectin was studied in 25 patients with psoriasis and 12 healthy subjects. The stimulation index of anti-CD3-mediated responses in the presence of type I collagen was about half that in the controls. Although the CD3-dependent proliferative response of psoriatic lymphocytes in patients with active widespread plaque psoriasis was reduced by about 50%, costimulatory responses induced by type IV collagen and fibronectin were found to be enhanced in relation to the controls. The degree of costimulation by type IV collagen and fibronectin was related to disease severity. The highest values of the stimulation index were found in patients with a PASI greater than 24, skin involvement of more than 40% of body surface area, and a duration of psoriatic lesions of more than 3 months. The results indicated that in active widespread plaque psoriasis subpopulations of T cells bearing receptors for some extracellular matrix proteins were increased in the peripheral blood. A factor responsible for this phenomenon may be trafficking of T cells through the basement membrane zone of psoriatic lesions, which presumably causes modification of T cell immunological responsiveness after recirculation.     

Regulation of the expression of epidermal keratinocyte proliferation and differentiation by vitamin A analogs

Summary A number of vitamin A analogs (retinoids) were used to manipulate the growth of epidermal keratinocytes in culture. The retinoids used were the TMMP analog of ethyl retinoate (Ro 10-9359), 13-cis retinoic acid, all trans retinoic acid and retinol (trans). These were added to primary neonatal mouse epidermal keratinocyte cultures that proliferate, stratify, and differentiate over 2–3 weeks. [³H]Tdr labeling technics were used to quantitate proliferation. A histologic stain, and a four buffer protein extraction protocol, used in conjunction with polyacrylamide gel electrophoresis and fluorographic technics, were used to assess the differentiation of the cultures. Our results showed that all of the vitamin A analogs we tested inhibited keratinocyte proliferation. Quantitation of specific differentiation proteins showed that Ro 10-9359 and 13-cis retinoic acid partially inhibited the differentiation of the cultures. The Ro 10-9359 retinoid was unusual in that it increased the synthesis of keratohyalin granule-related proteins. These studies showed that inhibition of basal cell proliferation did not result in the obligatory expression of cell differentiation and that at least one of the events that is a part of epidermal keratinocyte differentiation can be separately controlled.These data, in part, were presented at the Proceedings of the International Dermatology Symposium in Berlin, FRG, on October 13, 1980 [33]     

INFLUENCE OF VITAMIN E ON THE EFFECT OF VITAMIN A DERIVATIVES ON DIGESTIVE GLANDS OF RATS

This study was designed to investigate the influence of d-α-tocopheryl acetate on the toxic effect of retinoic acid and retinoid (Ro 10-9359) on pancreaticobiliary and gastric secretion after the administration of large doses for 3 weeks to albino rats. The toxicity of retinoic acid on body weight and exocrine function, and the morphologic changes in the main digestive glands of the rat are greater than with retinoid. It is clear that vitamin E may suppress or counteract the undesirable toxic effects of retinoic acid and retinoid and appears to promote the function of the main digestive glands of rats.     

Subcorneal pustular dermatosis (Sneddon-Wilkinson disease)—therapeutic problems

A patient with subcorneal pustular dermatosis with a fatal outcome is presented. Treatment with corticosteroids, vitamin E, dapsone, sulphapyridine and levamisole was ineffective. Only systemic treatment with retinoic acid and a new aromatic retinoic acid derivative (Ro 10-9359) produced a satisfactory clinical response, but a complete remission was not obtained.     

Therapy of psoriasis with retinoid plus PUVA: Clinical and histologic data

Summary In a group of 40 patients suffering from wide-spread psoriasis oral administration of a retinoid (Ro 10-9359) was followed by PUVA therapy. The clearance rate was increased by 30% as compared to PUVA alone. Except for cheilitis no side effects were seen. Histological analysis in 20 patients before, during and after therapy revealed an intensification of psoriatic tissue changes after retinoid treatment. Loss of corneal layers, massive exoserosis, and neutrophil migration were prominent features. Mitotic counts were not increased by the pretreatment. The increased susceptibility of diseased skin to PUVA as produced by this drug appears to be based on several factors related to the tissue changes revealed by histology.Presented at the Niels-Stenson-Symposion, Appenrade, Denmark, October 28, 1978     

Therapeutic evaluation of the oral retinoid Ro 10-9359 in several non-psoriatic dermatoses

Forty-five patients suffering from various genodermatoses and erythematous, scaling, non-psoriatic dermatoses were treated orally with the aromatic derivative of retinoic acid, Ro 10-9359 (Tigason). In the genodermatoses the best results were obtained in ichthyosis, keratodermias and Darier's disease (95.6% good to excellent). Among the erythematous scaling diseases, treatment was effective in lichen planus, parapsoriasis and pityriasis rubra pilaris (53.3% good to excellent results). In comparison with therapies previously employed Ro 10-9359 was more effective. No serious side-effects were noted.     

Combined treatment of psoriasis with a new aromatic retinoid (Tigason) in low dosage orally and triamcinolone acetonide cream topically: a double-blind trial

In a multicentre double-blind trial the effect of three therapy regimens was studied for 6 weeks in ninety psoriasis patients: (1) aromatic retinoid (Ro 10-9359) orally (0.50-0.66 mg/kg body weight) and placebo cream topically; (2) aromatic retinoid (Ro 10-9359) (same dosage) with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream; (3) placebo capsules with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream. Regimen 1 had virtually no effect and regimen 2 gave better results than regimen 3 for almost ail parameters, although statistical significance was reached for only some of them. The 6 week double-blind period was followed by an open study in which all patients were treated according to regimen 2. The clinical result could be maintained up to the end of the study (18 weeks), when more than 60% of the patients showed good to excellent (80–100%) improvement. Most of the patients had dry lips, but generally without clinical symptoms of a cheilitis. The other well-known side-effects of retinoid were mild and relatively rare. It is concluded that the combination of the aromatic retinoid (Ro 10-9359) given in low dosage orally with corticosteroids topically is as effective as therapy with the retinoid in high dosage alone, but with markedly less side-effects.