Intermittent short courses of cyclosporin (Neoral®) for psoriasis unresponsive to topical therapy: a 1-year multicentre, randomized study

We performed a 1-year study to determine whether intermittent short courses of the microemulsion formulation of cyclosporin (Neoral) could effectively control plaque psoriasis and whether tapering or abrupt cessation of cyclosporin therapy would influence time to relapse. Four hundred patients with plaque psoriasis were included in this open, multicentre, randomized study. All patients commenced cyclosporin at a dose of 2.5 mg/kg daily. Cyclosporin dosage could be increased to a maximum of 5 mg/kg daily. Treatment was continued until clearance of psoriasis or for a maximum of 12 weeks. Patients were then randomly assigned either to stop cyclosporin abruptly or to have the dose reduced by 1 mg/kg daily each week until cessation. On relapse, patients were given another course of cyclosporin. Patients were followed for at least 1 year, during which they could receive as many treatment courses as necessary. The number of patients who required one, two, three and four treatment courses was 400, 259, 117 and 26, respectively. The median time to relapse after the end of the first treatment period was 109 days in the group of patients randomized to stop cyclosporin abruptly and 113 days in patients randomized to taper off cyclosporin (P = 0.038). More than 30% of patients had not relapsed 6 months after having stopped treatment. After each treatment course, the Kaplan-Meier probability of achieving 75% or more reduction in disease area by day 84 of treatment was 83%, 76%, 73% and 66%, respectively. Mean serum creatinine concentration and blood pressure did not show any clinically significant changes over time. Our results show that intermittent short-course therapy with Neoral, when used in conjunction with topical therapy, is well tolerated and provides effective control of plaque psoriasis for 1 year. Tapering off cyclosporin on treatment cessation induces a slight delay in psoriasis relapse.     

Patients with psoriasis and their compliance with medication.

BACKGROUND: Poor compliance with treatment advice in chronic conditions, such as psoriasis, represents a major challenge to health care professionals. Previous research suggests that the rate of noncompliance in chronic conditions may be as high as 40%. OBJECTIVE: This study was designed to examine self-reported compliance in patients with psoriasis. METHODS: We undertook an anonymous postal survey sent to consecutive patients with psoriasis attending a tertiary psoriasis specialty clinic. RESULTS: Thirty-nine percent of participants reported that they did not comply with the treatment regimen recommended. The noncompliant group had a higher self-rated severity of psoriasis (t = -2.16, P =. 03), were younger (t = 3.28, P =.001), and had a younger age at onset (t = 2.35, P =.02) than those who were compliant. The noncompliant group reported that psoriasis had a greater impact on daily life (t = -2.23, P =.028), but general well-being was not significantly different from those who complied (t =.47, P = not significant). CONCLUSION: Patients who reported intentional noncompliance with treatment advice were more likely to believe that both psoriasis and its treatment interfered with their quality of life but not overall well-being. The impact of treatment on daily life highlights the importance of joint decision making in planning treatment.     

Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing

BACKGROUND: Langerhans cells (LCs) play essential roles in the initiation and regulation of cutaneous immune responses mediated through their successful migration from the epidermis to draining lymph nodes while carrying antigen. Tumour necrosis factor (TNF)-alpha, a keratinocyte-derived cytokine, has recently been shown to play an important role in the mobilization of LCs from human epidermis. Although it is known that with age the immune system changes, the influence of increasing age on the function of human LCs has not been defined clearly. OBJECTIVES: To examine the influence of age on the ability of TNF-alpha to induce LC migration. METHODS: Ten elderly (six men, four women; mean age 76 years, range 72-79) and 10 young (six men, four women; mean age 23 years, range 18-35) volunteers received intradermal injections of 200 U of human recombinant TNF-alpha diluted in sterile saline, and control injections of sterile saline alone, at each of two paired sites identified on photoprotected buttock skin. Two hours later, paired injection sites were excised by punch biopsy. One set of paired biopsies was processed for assessment of the frequency and morphology of epidermal LCs, following preparation of epidermal sheets and immunofluorescence staining for the LC marker CD1a. The remaining paired biopsies were processed in formalin and the inflammatory response to TNF-alpha was assessed by standard histological examination. RESULTS: Mean +/- SEM baseline values for LC frequency within epidermal sheets were significantly different between young (1156.3 +/- 38.5 cells mm(-2)) and elderly subjects (835.7 +/- 48.2 cells mm(-2); P < 0.01). Intradermal injections of 200 U of TNF-alpha caused a significant reduction in the frequency of LCs in both elderly and young subjects (P < 0.01). However, the extent of TNF-alpha-induced LC migration was substantially different between the two groups, with a mean 9% reduction in LC frequency in elderly volunteers compared with a mean 23% decrease in young subjects. Exposure to TNF-alpha was associated with a perivascular polymorphonuclear infiltrate at 2 h in all young subjects; in contrast, only 50% of the elderly individuals showed evidence of such a response. CONCLUSIONS: There are significant differences between young and old skin with respect to both resting LC numbers and their response to TNF-alpha. These age-related changes in LC frequency and function may contribute to the altered cutaneous immune function observed in the elderly.     

Fibrillin microfibrils are reduced in skin exhibiting striae distensae

Striae distensae (striae: stretch marks) are a common disfiguring condition associated with continuous and progressive stretching of the skin—as occurs during pregnancy. The pathogenesis of striae is unknown but probably relates to changes in those structures that provide skin with its tensile strength and elasticity. Such structures are components of the extracellular matrix, including fibrillin, elastin and collagens. Using a variety of histological techniques, we assessed the distribution of these extracellular matrix components in skin affected by striae. Pregnant women were assessed for the presence of striae, and punch biopsies were obtained from lesional striae and adjacent normal skin. Biopsies were processed for electron microscopy, light microscopy and immunohistochemistry. For histological examination, 7 μm frozen sections were stained so as to identify the elastic fibre network and glycosaminoglycans. Biopsies were also examined with a panel of polyclonal antibodies against collagens I and III, and fibrillin and elastin. Ultrastructural analysis revealed alterations in the appearance of skin affected by striae compared with that of normal skin in that the dermal matrix of striae was looser and more floccular. Light microscopy revealed an increase in glycosaminoglycan content in striae. Furthermore, the number of vertical fibrillin fibres subjacent to the dermal–epidermal junction (DEJ) and elastin fibres in the papillary dermis was significantly reduced in striae compared with normal skin. The orientation of elastin and fibrillin fibres in the deep dermis showed realignment in that the fibres ran parallel to the DEJ. However, no significant alterations were observed in any other extracellular matrix components. This study identifies a reorganization and diminution of the elastic fibre network of skin affected by striae. Continuous strain on the dermal extracellular matrix, as occurs during pregnancy, may remodel the elastic fibre network in susceptible individuals and manifest clinically as striae distensae.     

Interleukin-4 enhances the survival of severe combined immunodeficient mice engrafted with human B-cell precursor leukemia

Human interleukin-4 (huIL-4) has been shown to inhibit the growth in vitro of cells from patients with acute lymphoblastic leukemia (ALL). With the aim of determining whether this cytokine might be useful in the treatment of patients with ALL, the effects of huIL-4 on human B- cell precursor ALL engrafted in severe combined immunodeficient (SCID) mice were examined. The inhibition of [3H] thymidine uptake of primary ALL cells by huIL-4 was maintained following engraftment and passage of leukemia in SCID mice. Five of seven xenograft leukemias showed significant inhibition in vitro by huIL-4 at concentrations as low as 0.5 ng/mL; furthermore, huIL-4 counteracted the proliferative effects of IL-7. When used to treat two human leukemias engrafted in SCID mice, huIL-4 200 microgram/kg/d, as a continuous 14-day subcutaneous infusion, suppressed the appearance of circulating lymphoblasts and extended survival of mice by 39% and 108%, respectively, the first demonstration of IL-4 activity against human leukemia in vivo. The mean steady-state huIL-4 level in mouse plasma during the infusion was 1.46 ng/mL (SEM +/- 0.14 ng/mL), which was similar to concentrations found to be effective in vitro. ALL cells obtained from mice relapsing after huIL-4 treatment continued to show inhibition by the cytokine in vitro. These data suggest that IL-4 may be useful in the treatment of patients with ALL.     

Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. A clinical and immunopathologic analysis

Cyclosporine is known to be effective in the treatment of psoriasis. In this study, we have used oral cyclosporine (6 mg/kg per day) given for 5 to 30 weeks to 24 patients for the treatment of 12 different dermatoses. Patients with the following diseases demonstrated a marked response or total clearing: 1 patient each with pyoderma gangrenosum, pityriasis lichenoides chronica, and psoriasis of the acrodermatitis continua of Hallopeau type. Moderate to marked response occurred in both patients with epidermolysis bullosa acquisita and the patient with hidradenitis suppurativa. Minimal to moderate responses were obtained in both patients with granuloma annulare, 1 of 2 with acrodermatitis continua of Hallopeau, both patients with Darier's disease, and 1 of 6 patients with vitiligo. Little or no response was noted in both patients with sarcoidosis, all 3 patients with pityriasis rubra pilaris, 5 of 6 patients with vitiligo, 1 patient with pemphigus foliaceous, and 1 with pemphigus vulgaris. Clinical side effects were mild and transient and included dysesthesia, fatigue, hypertrichosis, nausea, and flushing. The most frequent clinically significant abnormalities were hypertension and renal dysfunction, with all factors normalizing within 1 month of discontinuation of cyclosporine therapy.     

Ambulatory monitoring of bladder and detrusor pressure during natural filling

We have developed a system to perform fully ambulatory monitoring studies of the bladder. Bladder and rectal pressures are recorded during natural filling of the bladder for up to 6 hours. This system has been evaluated in 19 studies performed on 15 patients. The mean duration of the studies was 3 hours 51 minutes (standard deviation +/- 1 hour 3 minutes) and the mean number of voids per patient was 3.8 +/- 2.2. Visual inspection of the recorded data showed that subtraction of the rectal trace from the bladder trace provided a useful detrusor trace when subjects were ambulant as well as resting. When ambulant, movement caused typical peak-to-peak pressure variability in the bladder and rectal traces of approximately 30 +/- 20 cm. water (mean and standard deviation of peak-to-peak pressure for typical ambulant 5-minute sections for each patient), which after subtraction was reduced on the detrusor trace to 10 +/- 5 cm. water. The equivalent figures when resting were 9 +/- 5 cm. water, subtracting to less than 5 cm. water for the detrusor. Further measurements also were calculated for the whole of each trace. The system provided good quality recordings and should prove useful in future evaluations of natural fill urodynamic studies.