Clobetasol propionate followed by calcipotriol is superior to calcipotriol alone in topical treatment of psoriasis.

BACKGROUND: Although potent, topical corticosteroids offer effective and rapid healing of psoriatic lesions. Their long term use is limited because of the risk of side effects. Calcipotriol is safe for long-term treatment, but its initial efficacy is lower than with topical corticosteroids. OBJECTIVES: To investigate whether 2 weeks of treatment with clobetasol propionate 0.05% ointment bd followed by 4 weeks of treatment with calcipotriol 50 microg/g bd would offer therapeutic advantages over 6 weeks of continuous treatment with calcipotriol. METHODS: Forty-nine patients with moderate to severe plaque psoriasis were recruited from five centres in Norway. In a randomised, double-blind, right- versus left-side comparison, ointments were applied to two symmetrically-located areas. RESULTS: Two weeks of treatment with clobetasol propionate produced a significantly greater decrease in total symptom score (combined scores of erythema, induration and scaling) than calcipotriol treatment (P < 0.0001). This improvement on the clobetasol propionate-treated side of the body was maintained throughout a subsequent 4-week treatment period when calcipotriol was applied to both sides of the body (P < 0.0001). The superiority of the clobetasol propionate followed by calcipotriol treatment was maintained during a 4-week, treatment-free, observation period. Treatments were well tolerated with no rebound effect. CONCLUSIONS: Clobetasol propionate ointment bd for 2 weeks followed by treatment with calcipotriol ointment bd for 4 weeks was superior to calcipotriol ointment alone in the treatment of plaque psoriasis.

Once daily treatment of psoriasis with tacalcitol compared with twice daily treatment with calcipotriol. A double-blind trial.

Once daily topical treatment of psoriasis with tacalcitol ointment (4 micrograms/g) was compared with twice daily treatment with calcipotriol ointment (50 micrograms/g) in a double-blind, randomized study over a treatment period of 8 weeks. The severity of pruritus, erythema, infiltration and scaling was scored on a scale from 0 to 4. These features were scored at the initiation of treatment, after 2, 4, 6 and 8 weeks of treatment, and at 4 weeks after discontinuation of treatment. The sum score was the total score for erythema, infiltration and scaling. Serum levels of calcium, phosphate, ionized calcium and intact parathyroid hormone were used as safety parameters. Two hundred and eighty-seven adults with stable plaque psoriasis participated and were treated at least once. Both tacalcitol and calcipotriol ointments effectively reduced the severity of psoriasis. The mean reduction in the sum score in the intention-to-treat population of 287 patients was 4.03 in the group treated with tacalcitol compared with 5.05 in the group treated with calcipotriol. The mean baseline sum scores were 7.64 and 7.15, respectively. The acceptability of both ointments was excellent, and none of the patients had adverse effects in terms of increased serum calcium or other alterations in calcium metabolism. Although less effective than calcipotriol ointment used twice daily, tacalcitol ointment is an effective and useful once daily treatment of chronic plaque psoriasis.

IgG-Fc receptors in stratum granulosum: an immunological defence in human skin?

Receptors for the Fc-part of IgG (Fc tau R) in stratum granulosum of normal human skin were examined using cryosections and indirect immunofluorescence staining with 1) soluble immune complexes and 2) monoclonal antibodies (MoAbs) against different types of Fc tau R, i.e. 32.2 (anti-Fc tau I-CD64), IV.3 (anti-Fc tau RII-CD32) and Leu 11b (anti-Fc tau RIII-CD16). The immune complexes gave staining corresponding to stratum granulosum in sections from all skin specimens. Inhibition experiments showed that pre-incubation of the sections with monomeric and heat-aggregated human IgG, periodic acid and formaldehyde inhibited the immune complex binding. F(ab')2 containing immune complexes did not bind to the skin sections. The MoAb 32.2 gave granular and Leu 11b linear staining corresponding to stratum granulosum. In addition, both IC, 32.2 and Leu 11b gave weaker staining of keratinocytes in other parts of the epidermis. IV.3 stained epidermal Langerhans' cells and were unreactive with other epidermal cells. Indirect immunofluorescence staining with MoAbs against IgG subclasses showed the presence of all IgG subclasses in stratum granulosum. The results show that granulosum cells express both high- and low-affinity IgG receptors and in vivo bound IgG. The data point to a role for stratum granulosum in cutaneous immunity.

[Immunopathogenesis of atopic eczema]. / Immunpatogenese ved atopisk eksem.

The role of elevated serum IgE in patients with atopic eczema has been unclear. It has recently been shown that antigens from house dust mites may penetrate the skin, bind to IgE on Langerhans' cells, which in turn mediate the activation of antigen-specific TH2 cells that are the predominant T cells found in early atopic skin lesions. TH2 cells produce IL-4, which stimulates the IgE production by B lymphocytes, and are chemotactic for eosinophilic granulocytes. The discovery of microbial superantigens that activate T cells more easily and less specifically than the traditional antigens do, helps us to understand how local microbial agents can provoke the outburst of new atopic skin lesions.

Fc gamma-receptors in skin and serum from patients with psoriasis, before and after therapy.

IgG-Fc receptors (FcR) are present on most immune competent cells. We have examined FcR in skin lesions from 8 patients with stationary plaque psoriasis and 12 patients with highly active psoriasis using MoAbs against FcR and binding of soluble immune complexes. FcR in serum were measured in ELISA. The patients were treated with cyclosporin (n = 5), acitretin (n = 7) and Goeckerman regimen (n = 8). As controls served 8 skin biopsies and 22 sera from healthy individuals. Highly active psoriatic lesions showed strongest activity for FcRI, II and III and immune complex binding. The FcR+ mononuclear cells were located perivascularly and along the dermo-epidermal junction. The FcR activity decreased in correlation to the improvement following therapy. Epidermal Langerhans cells (LC) were positive for FcRII and immune complex binding. FcR activity on LC decreased during therapy. Keratinocytes expressed FcRI and III, irrespective of disease activity and therapy. FcR levels were lower in sera from psoriatics than in controls, median 0.15 vs. 0.27 (p < 0.01), and not correlated to disease activity. In 4 patients the FcR levels increased during therapy. The reduced levels of FcR in psoriatic sera might be due to consumption in the skin or anti-FcR autoantibodies.

Serum levels of interferons and TNF-alpha are not correlated to psoriasis activity and therapy.

Sera from 52 patients with psoriasis and 106 controls were tested for IFN-tau, IFN-alpha 2 and TNF-alpha in ELISA and for total IFN activity using an infectivity inhibition micromethod. Psoriasis patients had lower serum levels of IFN-tau than had the controls: median 0.10 ng/ml vs. 0.16 ng/ml (p = 0.01). The highest median serum IFN-tau levels were in patients with peripherally spreading psoriasis, 0.10 ng/ml, and acute guttate psoriasis, 0.09 ng/ml. Patients with stable plaque psoriasis had lower serum IFN-tau levels (median 0.0) than those with other forms of psoriasis, or blood donors. The serum levels of IFN-alpha 2, total IFN activity and TNF-alpha did not differ between the psoriasis and control group. Treatment with cyclosporin, acitretin and the Goeckerman regimen increased the total IFN activity, but did not affect the levels of IFNs nor TNF-alpha.

[Cyclosporine in the treatment of psoriasis]. / Cyklosporin i behandlingen av psoriasis.

Psoriasis is a chronic inflammatory skin disease of unknown etiology. An immune-reaction mediated by T lymphocytes is important in the pathogenesis. Cyclosporin is a selective immuno-suppressant that inhibits helper T lymphocytes. Several controlled clinical studies have shown that cyclosporin is highly effective in controlling severe psoriasis. The main side effects are hypertension, nephrotoxicity and increased risk of developing malignancies, particularly after long-term treatment. Side effects during short-term therapy appear to be reversible. Some questions connected to the long-term use and safety of cyclosporin are still unsolved.

Fc gamma-receptors on Langerhans' cells and keratinocytes in suspension from normal skin characterized using soluble immune complexes and monoclonal antibodies.

Fc-receptors for IgG (FcR) on epidermal cells in suspension were studied using soluble immune complexes and monoclonal antibodies (MoAbs) against FcR I, FcR II and FcR III using an indirect immunofluorescence technique. The binding of immune complexes demonstrated that most Langerhans' cells (greater than 95%) and a proportion of keratinocytes (25 +/- 6%) expressed functional FcR activity. The reactivity with MoAbs showed that epidermal cells possess different types of FcR. Langerhans' cells reacted only with IV.3 (anti-FcR II/-CDw32). A varying percentage of keratinocytes reacted with 32.2 (anti-FcR I/-CD64) (18 +/- 10%), Leu 11b (anti-FcR III/-CD16) (19 +/- 6%) and B1D6 (against a placental FcR) (35 +/- 8%). Both with immune complexes and MoAbs the staining was strongest along the cell surface, but cytoplasmic staining was also regularly present. The data add further support to the contention that keratinocytes have an immune function. FcR on epidermal cells may play an immunoregulatory role interacting with isotypes and cytokines in the skin. Keratinocyte-produced soluble FcR could also be an immunological mediator.

The distribution of Fc gamma RI, Fc gamma RII and Fc gamma R III on Langerhans' cells and keratinocytes in normal skin.

The distribution of Fc-receptors for IgG (FcR) on human epidermal cells (EC) was characterized in situ using monoclonal antibodies (MoAbs) by indirect immunofluorescence staining of cryosections. The results showed heterogeneity of FcR expression on Langerhans' cells (LC) and keratinocytes (KC). The MoAb IV.3 against FcR II (CDw32) gave granular staining of most LC whereas the MoAb 32.2 against FcR I (CD64) occasionally stained a few dendritic cells. 32.2 demonstrated weak granular staining along the outer aspect of KC in stratum spinosum and stratum basale and intense staining of stratum corneum and stratum granulosum. The MoAbs Leu 11b against FcR III (CD16) and B1D6 reacting with a placental FcR with low affinity for IgG gave intense linear membrane staining of KC. Leu 11b produced strongest staining of stratum granulosum and B1D6 the strongest staining of stratum spinosum and basale. The results confirm our previous observations of FcR in situ on LC and KC in normal skin using functional assays and demonstrate that these EC possess different types of low affinity FcR. The data support the contention of an immune function of KC. FcR may be mediators for interaction between KC and LC. The FcR activity in stratum granulosum may have an immune function as a barrier against microorganisms and other antigens.

[Rosacea. Clinical features and treatment]. / Rosacea. Klinikk og behandling.

The paper describes clinical features, concepts in the pathogenesis, and therapeutical aspects of rosacea. Particular attention is paid to recent experiences on topical therapy with metronidazole. A Norwegian double-blind, multi-centre clinical trial compares metronidazole 1% cream applied twice daily with placebo cream in the treatment of 97 patients with rosacea. After eight weeks of treatment there was a statistically significant difference between the two regimens in favour of metronidazole cream. No important side effects were registered. It is concluded that 1% metronidazole cream is an effective and well-tolerated alternative to tetracycline in patients with papulopustular rosacea.

A double-blind comparison of acitretin and etretinate in the treatment of severe psoriasis. Results of a Nordic multicentre study.

Acitretin, the free acid of etretinate, is less lipophilic and has a much shorter terminal half-life than the parent compound. The present double-blind, randomized study compared the therapeutic effectiveness and the tolerability of acitretin (n = 127) and etretinate (n = 41) in psoriasis. Patients were treated with 40 mg daily for the first 4 weeks and with an individually adjusted dose for the subsequent 8 weeks. The average daily doses of acitretin (0.54 mg/kg/day) and etretinate (0.65 mg/kg/day) were similar. The PASI (Psoriasis Area and Severity Index) scores improved in parallel in the 2 treatment groups. At the completion of the study, the PASI score improvement was 75.8% for acitretin and 70.8% for etretinate. Both acitretin and etretinate resulted in mucocutaneous side effects. Assessments of tolerability by investigators and patients showed a statistically significant difference in favour of etretinate. These results demonstrate that acitretin and etretinate have similar therapeutic effectiveness in psoriasis. Although the tolerance to acitretin was lower than to etretinate, acitretin offers the important advantage of a much shorter period of potential teratogenicity and is, therefore, to be preferred in women of childbearing potential.

In situ localization of interferons in psoriatic lesions.

An indirect immunofluorescence technique, using murine monoclonal antibodies (MoAbs) against human IFN-alpha and human IFN-gamma was used to study IFNs in cryostat sections from psoriatic skin lesions. The IFNs were more pronounced in sections from highly active psoriasis than in sections from stationary psoriasis. In highly active psoriatic lesions IFN-alpha was localized to keratinocytes is stratum basale, to some epidermal dendritic cells, probably Langerhans cells, and to some mononuclear cells in dermis. IFN-alpha was usually not detected in sections from stationary psoriasis. IFN-gamma was localized to stratum corneum, to keratinocytes around microabcesses and to mononuclear cells in the dermal cell infiltrates, predominantly in highly active psoriatic lesions. Both IFN-alpha and IFN-gamma were localized to some endothelial cells in the papillary dermis. The MoAbs did not stain sections from unaffected skin from patients with psoriasis or sections from healthy individuals. The findings indicate that the IFN system in the skin may be of significance in the pathophysiology of psoriasis.

Fc gamma-receptor as a functional marker on epidermal Langerhans' cells in situ.

Fc gamma-receptors (FcR) in cryostat sections of normal human skin were detected with soluble immune complexes of horseradish peroxidase (HRP) and rabbit IgG anti-HRP (HRP-anti-HRP). The binding of HRP-anti-HRP to Langerhans' cells (LC) was demonstrated using a double immunofluorescence staining in which LC were identified with a CD1a specific monoclonal antibody (Leu 6). The immune complexes gave granular staining of CD1a+ epidermal cells in sections of all specimens from normal skin. The mean percentage of CD1a+ cells that were FcR+ was 49 +/- 11 (n = 8). The FcR+/CD1a+ cells had a clearly defined dendritic pattern. The staining intensity of LC with HRP-anti-HRP was weaker than the intense staining of CD1a-macrophages in the dermis. Results of inhibition experiments indicate that human epidermal LC express low affinity FcR, but the presence of high affinity FcR as well cannot be excluded. The demonstration of FcR expression on normal LC clarifies previous uncertainty on LC membrane receptors, though the functional significance of these receptors is still not well understood.

Immunological changes following treatment of psoriasis with cyclosporin.

Five patients treated for severe plaque psoriasis with cyclosporin were studied. Cryostat sections of biopsies taken from the same lesional skin areas before and during therapy were examined for immunological surface markers, and deposits of immunoglobulins and complement using a panel of monoclonal and polyclonal antibodies. Fc gamma-receptors (FcR) were detected using soluble immune complexes of horseradish peroxidase (HRP)-anti-HRP. During therapy the dermal accumulation of T-lymphocytes (CD3+, CD4+, CD8+ and IL2R+ cells), macrophages (OKM1+), CD1a+ and FcR+ cells decreased, paralleling clinical improvement. However, in normalized skin there were still patchy accumulations of mononuclear cells in some dermal papillae close to the dermo-epidermal junction. In the epidermis CD8+ and IL2R+ cells rapidly disappeared during clinical improvement. The numbers of epidermal dendritic CD1a+ and HLA-DR+ cells increased and their distribution pattern became regular. The percentage of CD1a+ epidermal cells expressing FcR was reduced during therapy. IgM deposits regularly found along the dermal vessels and the dermoepidermal junction before therapy gradually disappeared. Serum levels of IgA increased and C4 decreased, though not significantly. Serum levels of gamma-IFN, alpha 2-IFN and TNF remained unchanged. The findings indicate that cyclosporin inhibits various sides of the immune response.

Acitretin versus etretinate in severe psoriasis. A double-blind randomized Nordic multicenter study in 168 patients.

The efficacy and tolerability of acitretin (etretin) in severe psoriasis was compared with that of etretinate in a double-blind randomized study for 12 weeks. A total of 127 patients received acitretin and 41 received etretinate. The initial daily dose was 40 mg/day over 4 weeks and was subsequently adjusted according to individual response. From week 5-12 the mean daily dose was 42.9 mg of acitretin (0.58 mg/kg) versus 49.2 mg of etretinate (0.65 mg/kg). Acitretin gave a PASI score reduction from baseline of 70.5% and etretinate a reduction of 68.4% (mean values). Acitretin tended to give more discomfort than etretinate, particularly with regard to hair loss and peeling of palms and soles. The differences found between acitretin and etretinate may be related to higher maximum plasma concentrations of acitretin. The considerably shorter half-life of acitretin, gives it a great advantage over etretinate with regard to risk of teratogenicity after cessation of treatment.

Fc gamma-receptors and HLA-DR antigens on endothelial cells in psoriatic skin lesions.

Receptors for the Fc-part of IgG (FcR) and HLA-DR antigens on endothelial cells in normal and lesional skin from patients with psoriasis were studied in cryostat sections, using soluble immune complexes and monoclonal antibodies. FcR and HLA-DR antigens were detected on endothelial cells of dermal vessels both in sections of normal and lesional skin. The expression of FcR varied from one vessel to another and on endothelial cells within one and the same vessel. The expression of FcR and HLA-DR antigens was enhanced in sections of lesional skin compared with normal skin and most pronounced in lesional skin from active psoriasis. The enhanced expression may be mediated by interferon produced in psoriatic lesions. The presence of FcR and HLA-DR antigens on endothelial cells adds further evidence of he involvement of these cells in immune processes in the skin.

Effect of UV radiation on interferon, immunoglobulins and complement components in serum from healthy individuals.

An infectivity inhibition micro-method was used to detect interferon (IFN) in sera from 20 healthy individuals before and after UVA irradiation, and in sera from 22 healthy individuals before and after UVB irradiation. The serum levels of IFN, immunoglobulins (Ig) and complement components (C) were examined before irradiation, after 10 and 20 exposures, and 4 weeks after irradiation. The median serum IFN level in both the UVA and the UVB group increased significantly during irradiation, most markedly during the 10 first exposures. Four weeks after irradiation the median IFN level was reduced in both groups, but had not reached the pre-irradiation levels. The IFN level was unchanged or reduced in 2 individuals in the UVA group and in 5 individuals in the UVB group. Characterization experiments indicated the presence of both acid-stable and acid-labile IFN-alpha and IFN-gamma. The mean serum IgG concentration was significantly reduced 4 weeks after UVA irradiation, whereas IgA, IgM, C3 and C4 were not affected. The mean serum concentrations of IgG and C4 were significantly reduced 4 weeks after UVB irradiation, whereas the mean concentrations of IgM and C3 were significantly increased. The concentration of IgA was not affected.

The effect of Goeckerman therapy on interferon in serum and suction blister fluid from patients with psoriasis.

An infectivity inhibition micromethod was used to detect interferon (IFN) in sera and suction blister fluids from 35 patients with untreated psoriasis vulgaris. IFN (greater than or equal to 16 units/ml) was detected in 56% of the sera (median 25 units/ml), in 77% of the suction blister fluids from lesional skin (median 35 units/ml) and 33% of the blister fluids from unaffected skin (median 10 units/ml). IFN levels were significantly higher in blister fluids from lesional skin than from unaffected skin (P less than 0.05) indicating local IFN production. Results of characterization experiments indicated the presence of both acid stable and acid labile IFN-alpha as well as IFN-gamma in sera and blister fluids. After Goeckerman therapy, IFN was detected in 91% of the sera (median 89 units/ml), in 90% of the blister fluids from lesional skin (median 50.5 units/ml) and in 72% of the blister fluids from unaffected skin (median 26.5 units/ml). The IFN levels in sera were significantly higher than in blister fluids from both lesional skin (P = 0.05), and unaffected skin (P = 0.001). Furthermore, after Goeckerman therapy the IFN levels in blister fluids from unaffected skin and in sera were significantly higher than those in untreated patients (P = 0.01 and P = 0.0001) respectively. The results indicate that UVB radiation induces systemic IFN production.