Biomedical subjects
Publications and source records attributed to M A De Rie.
Generalized angiokeratoma are associated with three lysosomal storage disorders, one of which is Fabry disease (alpha-galactosidase A deficiency). Treatment for Fabry disease with supplementation of recombinant enzyme is available in the European Union and subsequently physicians' awareness may rise. A patient who was erroneously diagnosed with Fabry disease is presented.
BACKGROUND: Necrobiosis lipoidica (NL) is a rare skin disease, mostly seen on the legs and often occurring in patients with diabetes mellitus. The disease belongs to the idiopathic cutaneous palisading granulomatous dermatitides associated with a degeneration of collagen, thus leading to skin atrophy. Application of topical corticosteroids is the most widely used treatment but the results are not always satisfactory and may worsen skin atrophy. Preliminary studies in patients with NL have shown a clinical response with psoralen plus ultraviolet (UV) A (PUVA). Objectives To study the effect of topical PUVA on NL in a multicentre prospective study. METHODS: Thirty patients (27 women and three men) including 13 with insulin-dependent diabetes mellitus, with a diagnosis of NL proven by histopathology, were included. All patients had been unsuccessfully treated with topical and/or intralesional corticosteroids. Patients were treated twice weekly with an aqueous gel containing 0.005% psoralen followed by irradiation with UVA. Clinical photographs were taken for evaluation. In addition, 20-MHz high-frequency ultrasound analysis was performed in 10 patients to evaluate the thickness and density of the dermis during topical PUVA therapy. RESULTS: Five patients (17%) showed complete clearing (healing of ulceration and disappearance of erythema) after a mean of 22 exposures (range 15-30). Eleven patients (37%) showed improvement, defined as healing of ulceration and/or reduction of erythema, after a mean of 23 exposures (range 11-42). Ten patients (33%) showed no effect and four patients (13%) worsened during topical PUVA therapy. The treatment results of the patients who suffered from diabetes mellitus were not different from those who did not have diabetes mellitus. No difference was seen in mean dermal thickness (1666 vs. 1706 micro m) and density (17 vs. 16 units) before and after topical PUVA therapy. Side-effects were seen in 10 patients: hyperpigmentation (n = 4), blistering (n = 4) and bacterial infection (n = 2). CONCLUSIONS: Topical PUVA may be a useful treatment modality for NL in patients not responding to topical or intralesional corticosteroids.
Results of ultraviolet (UV) B phototherapy can be improved by the application of calcipotriol, but studies are needed to decide how the two treatments should be combined. We studied the effect of UVB after application of calcipotriol ointment (50 microg g-1) and calcipotriol cream (50 microg g-1) and determined the optimal time of application of calcipotriol when combined with UVB phototherapy (280-350 nm), in a single-blinded randomized vehicle-controlled study of 37 healthy adult volunteers. Calcipotriol ointment or cream was applied randomly on five areas on the back at different time intervals from UVB irradiation. One area was left untreated as the control. Application times were the evening before, the morning before, 2 h before, immediately before, and immediately after irradiation. UVB irradiation was administered by TL20W/12 fluorescent tube lamps at increasing doses (20, 25, 32, 40, 50 and 64 mJ cm-2) to six subunits of each test area. Clinical assessment was performed 24 h after UVB irradiation by a blinded investigator. Calcipotriol ointment and cream were applied in 19 and 18 subjects, respectively, and erythema was measured for each application time quantified. We found that erythemal reactions were significantly smaller when calcipotriol ointment or cream was applied immediately before irradiation compared with all other application times. To explain these findings, a vehicle control study was performed. No difference in erythema was seen between calcipotriol medication and the vehicle controls. Spectrophotometric analysis of the calcipotriol cream and ointment showed no UV absorbance in the UVB range. No signs of photosensitization were noted. In conclusion, the vehicles of the calcipotriol ointment and cream inhibit the induction of erythema by UVB irradiation if applied immediately before phototherapy. Consequently, calcipotriol ointment and cream should not be applied directly before UVB irradiation; however, they may be applied at any time up to 2 h prior to or immediately after UVB irradiation. Possible explanations for this sunscreen activity are discussed.
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Activated T lymphocytes are thought to be involved in the pathogenesis of psoriasis. From studies with peripheral blood T lymphocytes it is known that T cells show a decrease in membrane expression of CD27 molecules during continuous antigenic stimulation. The T-cell activation molecule CD28 is thought to be involved in the transduction of an antigen-non-specific costimulatory signal. Therefore, in order to elucidate further the pathogenesis of psoriasis we studied the expression of CD27 and CD28, together with CD4, CD8 and CD45RA in this benign inflammatory dermatological disease. We used immunohistochemical techniques to determine absolute numbers of T lymphocytes and expression of these T-cell activation and T-subset-specific molecules in normal (n = 7), uninvolved perilesional (n = 7) and lesional psoriatic (n = 7) skin. We found that not only lesional but also clinically uninvolved perilesional skin showed an increased number of T cells. Further, immunohistochemical studies showed that CD27 is expressed by a minority of normal skin T cells, while in lesional psoriatic skin, expression was even lower, and almost absent in perilesional skin sections. In contrast to normal skin, both perilesional and lesional psoriatic skin contained no CD28 positive T cells. In lesional psoriatic skin, however, T cells showed predominantly the CD4 phenotype, while in perilesional skin CD8 positive T cells were dominant. Two conclusions were reached: first, the absolute number of T cells, their CD27, CD28 and CD45RA expression, and the influx of CD8 positive T cells, indicate that perilesional psoriatic skin is different from normal and lesional psoriatic skin; and secondly, the data on CD27 and CD28 suggest that not only lesional but also perilesional psoriatic skin is subject to continuous antigenic stimulation, thus leading to decreased CD27 and CD28 expression on skin T cells.
An open, randomized trial was performed to determine the optimal dosage schedule with regard to the efficacy and safety of cyclosporin in severe atopic dermatitis. The study also provided clinical experience with regard to the efficacy and safety of long-term cyclosporin treatment. During a 2-month dose-finding period, 78 patients with severe, long-standing atopic dermatitis received cyclosporin at a dose of either 5 mg/kg per day, decreasing to 3 mg/kg per day (Group A), or 3 mg/kg per day, increasing to 5 mg/kg per day (Group B), Patients were maintained on their optimal dose for a further 10 months. Patients in Group A showed a significantly greater improvement in efficacy parameters over the first 2 weeks than with patients in Group B, but as the dose was decreased in Group A and increased in Group B, these differences were minimized. After 1 year, cyclosporin showed an efficacy of 59.8% in Group A and 51.7% in Group B, assessed by a severity score. Assessed in terms of an area score, these figures were 48.7% and 40%, respectively. Cyclosporin demonstrated a good safety profile during long-term treatment and was generally well tolerated. The lower starting dosage was not associated with higher dropout rates. This study showed no differences in efficacy or adverse events between the two dosage schedules in long-term treatment.
Psoriasis is a T-cell-mediated inflammatory skin disease which can be treated successfully with immunosuppressive drugs. Our purpose was to evaluate disease activity of psoriasis and the effect of immunosuppressive treatment by monitoring the soluble T-cell products sIL-2R, sCD27, sCD4, sCD8 and sICAM-1. Twenty-two patients were treated orally with escalating dosages of cyclosporin A (n = 17)(3-5 mg/kg/day) or FK506 (n = 5)(0.05-0.15 mg/kg/day). The Psoriasis Area and Severity Index (PASI) was used to monitor clinical activity of psoriasis. Serum samples were analyzed by ELISA. sIL-2R levels showed the highest correlation with psoriasis disease activity (rs = 0.89; p < 0.05). The longitudinal part of this study showed that levels of sIL-2R and sCD27 decreased during immunosuppressive treatment but remained above normal even in patients successfully treated. Our data indicate that sIL-2R levels are well correlated with disease activity in patients with psoriasis. sIL-2R levels closely follow the decrease of disease activity during immunosuppressive treatment.
Topical photochemotherapy with psoralen and its derivatives 4,5',8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP), with UVA irradiation, was evaluated with regard to minimum phototoxic dose, concentration, timing of UVA irradiation and systemic and local side-effects, in healthy volunteers. Psoralen (0.005%) in aqueous gel was found to be superior to TMP and 8-MOP in aqueous gel. No hyperpigmentation was seen after topical PUVA treatment with psoralen in aqueous gel. Patients with plaque-type psoriasis (n = 7), palmoplantar psoriasis (n = 7) and hyperkeratotic eczema (n = 2) were treated. Topical PUVA therapy was effective in most psoriasis patients, without the occurrence of local or systemic side-effects. Moreover, hyperkeratotic eczema patients who did not respond to conventional therapy showed partial remission. These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema.
Since oral cyclosporin A (CsA) has demonstrated its effectiveness in psoriasis and atopic dermatitis, efforts have been made to develop a topical CsA formulation, thus avoiding systemic adverse events. A limited number of publications are available on the use of topical CsA in allergic contact dermatitis and atopic dermatitis. Moreover the response rate of humans to topical CsA is about 50% or less. We now report our results with three new topical CsA formulations on allergic contact dermatitis and atopic dermatitis. No significant improvement was found in 16 atopic dermatitis patients and 7 allergic contact dermatitis (nickel sulphate) patients.
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Oral cyclosporin A (CyA) is highly effective in the treatment of psoriasis. The long-term use is limited by dose-dependent side-effects, and the local concentration of CyA is a determining factor in treatment. The concentration of CyA in suction-blister fluid (SBF) and in whole blood was assessed using a polyclonal radioimmunoassay (RIA). This was carried out in patients with psoriasis following a single dose of CyA and while on adequate oral treatment with the drug. Peak blister fluid levels ranged from 32 to 170 ng/ml, and whole blood levels from 1250 to 2540 ng/ml. CyA trough levels (12 h following taking the drug) in the blister fluid ranged from 22 to 113 ng/ml, and in whole blood from 148 to 935 ng/ml. The trough concentrations in SBF were approximately 10% of whole blood trough levels.
Anti-CD27 monoclonal antibodies react with a cell surface molecule expressed on medullary thymocytes and a large subpopulation (75%) of peripheral blood T lymphocytes. This study was undertaken to analyze the functional capacities of CD27+ and CD27- subpopulations within the CD4+ subset. In addition, we investigated whether CD27 subpopulations belong to two mutually exclusive T cell sublineages. Proliferation upon lectin stimulation by either phytohemagglutinin or pokeweed mitogen (PWM) was found to be consistently higher in CD4+CD27+ cells compared to CD4+CD27- cells. In contrast, CD27+ and CD27- cells did not differ in anti-CD3, soluble antigen or interleukin (IL)2-induced proliferation. In PWM-driven B cell differentiation, CD4+CD27+ cells provided helper activity on IgM production, while CD4+CD27- cells did not. The differences observed between CD4+CD27+ and CD4+CD27- cells in both proliferation and T helper activity on IgM production can, at least in part, be explained by the inadequate production of IL2 by CD27- cells upon lectin stimulation. In contrast, CD27+ and CD27- subpopulations did not differ in the production of interferon-gamma. CD27- cells could be induced to express the CD27 antigen through stimulation of these cells with immobilized anti-CD3 antibodies. After 3 days of culture, approximately 50% of the cells had CD27 membrane expression, whereas after 6 days 80% of the cells express the antigen. We conclude that anti-CD27 antibodies identify two functionally distinct T cell populations within the CD4+ subset. These subpopulations apparently do not belong to two separate T cell sublineages, but may reflect differences in the activation state of CD27+ vs. CD27- peripheral blood T lymphocytes.
A panel of five monoclonal antibodies (Mab) and a polyclonal antiserum directed against HLA class II were studied for their effect on growth of mature neoplastic B cells of prolymphocytic origin (B-PLL cells). The polyclonal antiserum and three out of five monoclonal antibodies were able to synergize with phorbol myristate acetate (PMA) to induce proliferation of B-PLL cells of one patient. Cross-blocking experiments showed that the proliferation-inducing Mab recognized closely related epitopes on HLA class-II molecules. The other two monoclonal antibodies recognized different epitopes on HLA class-II molecules and had no effect on proliferation of B-PLL cells. Proliferation induced by the combination of PMA and anti-HLA class-II Mab was inhibited by anti-CD18 (LFA-1) antibodies and was extremely dependent on cell density. This study indicates that certain HLA class II determinants on neoplastic B cells can transduce growth-promoting signals.
A procedure is described for the purification of monoclonal antibodies (Mab) from ascitic fluids, which meets the quality control required for in vivo applications of immunoglobulins (Ig) in man. Additional assays were performed to calculate viral and DNA content of the purified Mab. These studies are important to prevent the possible side effects, oncogenic events and virus-related diseases which could follow immunotherapy with Mab.
We produced and characterized a panel of anti-HLA class II monoclonal antibodies (mAb) to study the inhibition of T cell-dependent B cell differentiation. The newly produced mAb belonged to different isotypes and subclasses, and recognized at least two different nonpolymorphic HLA class II determinants. We found that anti-HLA class II mAb inhibited the pokeweed mitogen (PWM)- and interleukin 2-driven T cell-dependent IgM synthesis, but did not affect the phorbol myristate acetate-, phytohemagglutinin-, anti-T3- or PWM-induced T cell proliferation. Moreover, when the mAb were tested in a monocyte-independent B cell differentiation assay in which T cells are activated by insoluble anti-T3 mAb in the absence of accessory cells, no effect was seen on IgM synthesis. These data indicate that inhibition of T cell-dependent B cell differentiation by anti-HLA class II mAb is caused by interference with an accessory cell function essential for B cell differentiation.