Cyclosporine as maintenance therapy in patients with severe psoriasis.

BACKGROUND: Low-dose cyclosporine therapy for severe plaque psoriasis is effective. Most side effects can be controlled by patient monitoring, with appropriate dose adjustment or pharmacologic intervention, or both, if indicated. Prevention or reversibility of laboratory and chemical abnormalities may be achieved by discontinuation of therapy after the induction of clearing. However, relapse occurs rapidly on discontinuation. Maintenance therapy with cyclosporine after induction has not been fully evaluated. OBJECTIVE: Our purpose was to compare a regimen of 3.0 mg/kg per day of oral cyclosporine with placebo in maintaining remission or improvement in patients with psoriasis. METHODS: After a 16-week unblinded induction phase in which 181 patients received cyclosporine, 5.0 mg/kg per day (an increase up to 6.0 mg/kg per day and a decrease to 3.0 mg/kg per day were allowed, if required, to achieve efficacy or tolerability, respectively), those patients showing a 70% decrease or more in involved body surface area (BSA) entered the 24-week maintenance phase and were randomly assigned to either placebo, cyclosporine, 1.5 mg/kg per day, or cyclosporine, 3.0 mg/kg per day. Patients were considered to have had a relapse when BSA returned to 50% or more of the prestudy baseline value. Clinical efficacy, adverse effects, and laboratory values were monitored regularly throughout both study phases. RESULTS: During induction, cyclosporine at approximately 5.0 mg/kg per day produced a reduction in BSA of 70% or more in 86% of the patients. During maintenance, the median time to relapse was 6 weeks in both the placebo and cyclosporine 1.5 mg/kg per day groups, but was longer than the 24-week maintenance period in the 3.0 mg/kg per day group (p < 0.001 vs placebo). By the end of the maintenance period, 42% of the patients in the 3.0 mg/kg per day cyclosporine group had a relapse compared with 84% in the placebo group. Changes in laboratory values associated with the higher induction dosage generally exhibited partial or complete return toward mean prestudy baseline values during the maintenance phase, with the greatest degree of normalization in the placebo group. CONCLUSION: Cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day.

Angiogenic activity is defective in monocytes from patients with alopecia universalis.

Monocyte/macrophages are important components of cell-mediated immune responses in presentation of antigen, as regulators of lymphocyte function, and as sources of cytokines that modulate functions of cells other than those of the immune system. Their role in the pathogenesis of alopecia areata (AA) and universalis (AU) has not been explored. This study is an investigation of the function of peripheral blood monocytes from normal subjects and patients with AA, AU, and alopecia totalis (AT), with respect to the principal macrophage-derived angiogenic factor, tumor necrosis factor alpha (TNF alpha). Because neovascularization is a necessary component in the anagen phase of hair growth and may play a role in the pathology of these disorders, we asked whether monocyte/macrophage angiogenic activity was compromised in these alopecias. Purified preparations of monocytes were activated in culture. Conditioned media were assessed for angiogenic activity on the chick chorioallantoic membrane and for concentration of TNF alpha by enzyme-linked immunosorbent assay (ELISA). Both angiogenic and the TNF concentration were significantly diminished in conditioned media from AU monocytes when compared to those from normal subjects and patients with AA. These results show that the function of AU monocytes may be abnormal and that the abnormality may distinguish AU from AA. Defective monocyte/macrophage function could also play a pathogenic role via effects on neovascularization and/or modulation of the immune response.

Treatment of resistant severe psoriasis with systemic cyclosporine.

Four patients with severe psoriasis have been treated with oral cyclosporine for 6 months. Two had generalized erythroderma and two had extensive plaque-type psoriasis; all had either become unresponsive to or were unable to use other accepted treatments. All four patients responded rapidly and were completely clear of psoriasis within 3 weeks of beginning therapy. Initial doses ranged from 7.5 to 8.5 mg/kg/day. Mild reversible nephrotoxicity occurred in the one patient whose cyclosporine trough level briefly exceeded 200 ng/ml. Cyclosporine may offer an alternative therapeutic modality in the management of erythrodermic or severe resistant plaque-type psoriasis. The effectiveness of cyclosporine in psoriasis underscores the putative role of cell-mediated immune factors in the pathogenesis of psoriasis.

Systemic absorption of topical steroids. Metabolic effects as an index of mild hypercortisolism.

This study was undertaken to determine whether the commonly used treatment of psoriasis with potent topical glucocorticoids results in hypercortisolism and whether metabolic changes might provide a means for monitoring pharmacologic effects of excessive systemic absorption of glucocorticoids. Plasma cortisol, glucose, and insulin and circulating polymorphonuclear leukocytes were assessed under controlled conditions in five otherwise healthy patients with psoriasis (40% to 85% involvement) treated with topical desoximetasone, without occlusion. In all patients, there were rapid and sustained suppression of endogenous cortisol production, twofold to threefold increases in fasting insulin levels indicating insulin resistance, and elevated levels of polymorphonuclear leukocytes. Two patients also experienced reduced glucose tolerance. These findings suggest that application of potent corticosteroids to large areas of diseased skin results in sufficient systemic absorption to cause not only adrenal suppression but some degree of hypercortisolism with greater frequency and rapidity than has been suggested. Prospective monitoring of insulin-glucose relationships as a sensitive index of the metabolic effects of glucocorticoids may provide a means of assessing excess systemic absorption that is not predictable on the basis of adrenal suppression or circulating levels of the drug. Such prediction could have particular relevance in anticipating adverse clinical effects in the treatment of chronic skin disorders with potent topical glucocorticoids.

Lipid composition and acid hydrolase content of lamellar granules of fetal rat epidermis.

Lipids and acid hydrolases have been characterized in a subcellular fraction, enriched with lamellar granules (LG), derived from fetal rat epidermis. This fraction contains 23% glycosyl ceramides and ceramides, 15% free sterols, and 34% phospholipids. The lipid/protein ratio is 2.0. The sterols and sphingolipids were present in proportions similar to those previously reported in stratum corneum. These findings provide direct biochemical evidence for the widely accepted hypothesis that stratum corneum lipids are derived from exocytosis of lamellar granules into the intercellular space. The LG fraction was enriched in certain acid hydrolases including glucosidase, acid phosphatase, phospholipases A, and sphingomyelinase; other acid hydrolases, i.e., amino-glycosidases, glactosidase and aryl sulfatase (pH 5.5), and steroid sulfatase were not preferentially localized in this fraction. By modulation of phospholipids, glycolipids, and proteins in the membrane regions of stratum corneum, the acid hydrolases of LG may play a role relevant to the function and desquamation of stratum corneum.

Sphingolipids of the stratum corneum and lamellar granules of fetal rat epidermis.

Sphingolipid profiles have been determined for whole epidermis, a subcellular fraction enriched in lamellar granules, and a fraction enriched with stratum corneum derived from fetal rat skin. In each case, 4 groups of glucosylceramides and 6 groups of ceramides have been identified by thin-layer chromatographic comparison with structurally defined sphingolipids from pig epidermis. The relative amounts of the sphingolipids in each preparation have been quantified by photodensitometry of the charred chromatograms. Lamellar granule sphingolipids had elevated proportions, relative to whole epidermis, of acylceramides, acylglucosylceramides, and a glucosylceramide fraction which may be produced by O-deacylation of the acylglucosylceramides. The fetal stratum corneum-enriched samples contain reduced proportions of all glucosylceramides and acylceramides as compared to lamellar granule lipids. The possible functions of these sphingolipids in the assembly and structure of lamellar granules are discussed.

Effect of retinoic acid and low calcium conditions on surface glycoconjugates defined by differential lectin labelling in mouse epidermal cell culture.

The appearance of cell surface glycoconjugates (detected by fluorescein-isothiocyanate-conjugated lectins and bullous pemphigoid antibody) was serially examined in mouse epidermal cell cultures treated with trans-retinoic acid and aromatic retinoic acid (etretinate) and in cultures maintained under low calcium conditions. The changes in lectin staining occurred in concert with the process of differentiation as assessed by cell morphology and colony growth characteristics, and they correlated with the patterns observed in whole mouse skin. The keratocyte cultures treated with retinoic acid showed delayed and reduced differentiation and stratification, and this was associated with markedly reduced binding of lectins specific for N-acetyl-glucosamine and fucose. The low calcium concentration produced similar changes. Thus, the loss of surface glycoconjugates in the epidermal cell culture system was not specific for either retinoic acid or low calcium, but correlated with the degree of cell differentiation.

Cutaneous sarcoidosis associated with sarcoidosis of the upper airway.

The diagnosis of laryngeal sarcoidosis is frequently delayed because it is rare and often develops insidiously. A 24-year-old woman with the annular scarring form of cutaneous sarcoidosis later contracted laryngeal sarcoidosis. Despite a two-year history of upper respiratory tract symptoms, the patient's progressive respiratory distress was attributed to sarcoidal pulmonary involvement. Dermatologists should be aware of the risk of airway obstruction from laryngeal granulomas in patients with cutaneous sarcoidosis. Although most commonly associated with the lupus pernio form of sarcoidosis, upper airway granulomas also develop in patients with other cutaneous manifestations of sarcoidosis.

Acid hydrolases of the epidermis: subcellular localization and relationship to cornification.

Three lysosomal-type acid hydrolases were examined in subcellular fractions of the developing epidermis of fetal rats to assess the relationship of degradative enzymes to cornification. As the granular layer developed and cornified between 18 and 20 days (D) of gestation, epidermal acid phosphatase increased, acid phospholipase A remained constant, and beta-glucuronidase activity declined. The enzymes were present in 3,000, 17,000, and 100,000 g particulate fractions and soluble cytoplasm. However distribution differed: acid phosphatase and phospholipase A were more preferentially localized than was glucuronidase in the 17,000 g fraction which excluded mitochondria and ribosomes and was enriched in lamellar granules. The findings suggested that acid phosphatase and phospholipase were present in membrane-bound organelles (e.g., lamellar granules) in the granular layer. Particulate acid phosphatase increased with granular layers on days 19 and 20 while a 7-fold increase in soluble enzyme coincided with cornification on day 20. As shown by isoelectric focusing, the enzyme became more heterogeneous at day 20 than at day 18, suggesting increased glycosylation. The particulate fraction displayed lysosomal characteristics with respect to release of acid phosphatase, which was inhibited by hydrocortisone and enhanced by retinol. When fetal epidermis was allowed to cornify in organ cultures, similar increases in acid phosphatase occurred. The presence of hydrocortisone did not affect increase in total enzyme but a greater proportion remained in the particulate fraction. The findings suggest that particulate acid phosphatase and phospholipase are compartmentalized in organelles with lysosomal characteristics during development of granular cells and that release of phosphatase is coincident with cornification. This may reflect not only exocytosis of lamellar granules but also intracellular release of the hydrolytic enzyme.

Iatrogenic hyperadrenocorticism during topical steroid therapy: assessment of systemic effects by metabolic criteria.

Systemic absorption of topically applied glucocorticoids in quantities sufficient to replace endogenous production is not uncommon. However, iatrogenic Cushing's syndrome resulting from the use of topical corticosteroids is very rare. Thus the possibility that systemic absorption may cause hyperglucocorticism has been deemphasized and examined only sporadically. We have studied changes in carbohydrate metabolism induced by topical glucocorticoids in a psoriatic patient who had developed Cushing's syndrome from topical desoximetasone (Topicort). The results indicated that (1) fasting hyperglycemia and increased insulin-glucose ratios could be induced within 24 hours of administration of topical glucocorticoids, (2) insulin resistance accompanied abnormal carbohydrate tolerance, and (3) fluctuations in circulating leukocytes paralleled the changes in carbohydrate metabolism. The findings suggest that metabolic indexes of glucocorticoid action action may provide useful parameters for assessing systemic absorption of topical glucocorticoids. glucose relationship as one such index to assess the risk of treatment of extensive chronic skin disease with potent topical glucocorticoids.

A method for partial purification of lamellar granules from fetal rat epidermis.

A subcellular fraction enriched with lamellar granules was obtained from homogenates of fetal rat epidermis by means of density gradient fractionation in metrizamide. 62% of organelles in this fraction were bounded by single membranes and measured 80-130 nm in the shorter diameter. About 10% of these had characteristic lamellae. Other structures in this fraction were larger vesicles (20%) or smaller organelles and vesicles (18%). The fraction had a low buoyant density (1.08-1.10) suggesting a high lipid content and contained a sharply localized peak of acid phosphatase activity. The 80-130 nm organelles reacted with bismuth after oxidation with periodic acid and were positive for acid phosphatase. Other intracellular organelles (e.g., lysosomes, mitochondria, ribosomes) as well as keratin fibrils and keratohyalin were not present. It is concluded that most of this fraction consists of lamellar granules, permitting for the first time detailed investigations of the composition and metabolism of these organelles.

The phospholipases A of epidermis.

Phospholipases A have been characterized in fetal rat epidermis. Both a calcium dependent phospholipase A with pH optimum of 8.5 and a calcium independent enzyme with a pH optimum of 4.5 were found. Activity against both acyl groups of phosphatidyl choline were found for both enzymes and the findings suggested that the acid enzyme (pH 4.5) is primarily phospholipase A1. The specificity of the alkaline enzyme with respect to acyl groups could not be determined due to the marked hydrolysis of lysophosphatidyl choline. Lysophospholipase activity had similar pH and calcium requirements as the alkaline phospholipase A and the 2 activities could not be dissociated in these experiments. The acid phospholipase was localized primarily in a fragile large particle fraction while the alkaline enzyme was present in various subcellular fractions and most active in the soluble supernatant. These findings demonstrate that epidermal phospholipases A are similar to those in other mammalian tissues. The presence of both acid and alkaline enzymes ar various subcellular loci suggest that the enzymes may play important roles in many facets of epidermal membrane metabolism and in particular in the degradative events of keratinization.

Flux of fatty acids during epidermal differentiation.

Fetal rat skin prior to cornification (18 days of gestation) was prelabeled with [14C] linoleic acid in vitro and subsequently allowed to differentiate and cornify in organ culture. During 48 hr in culture total epidermal 14C fatty acids and 14C dienes decreased in phospholipids and increased in triglycerides and sterol esters as granular layers and stratum corneum formed. During the second 24-hr period, there was no net loss in 14C fatty acids from the epidermis, suggesting that the changes in phospholipid and neutral esters represented translocations of fatty acids within the cornifying cells. The findings are consistent with the hypothesis that fatty acids liberated by hydrolysis of phospholipids are salvaged by reesterfication as neutral lipid esters during epidermal cornification.

Changing patterns of incorporation of (14C)histidine and (3H)leucine into epidermal proteins during differentiation of fetal rat skin.

Synthesis of epidermal proteins has been assessed during epidermal differentiation in fetal rat skin by studies of the simultaneous incorporation of [14C]histidine (H) and [3H]leucine (L) in vitro. Relative incorporation of the two amino acids into epidermal proteins was assessed in terms of H/L ratios and absolute rates of incorporation related to DNA content. Biochemical parameters were correlated with morphologic development. An increase in incorporation of both amino acids accompanied stratification and development of granular and cornified layers between 18 days of gestation and 3 to 5 days postpartum. Relatively greater incorporation of histidine after development of mature granular cells and stratum corneum was reflected in increasing H/L ratios. These results correlated with negative Pauly staining of the initial fetal keratohyaline granules at day 18 and positive staining of mature granules at subsequent stages of development. H/L ratios appear to represent a sensitive marker for differential protein synthesis during differentiation in whole epidermis. The results suggest that biosynthesis of histidine-rich protein is associated with production of mature keratohyaline granules during fetal development.