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Background: There is evidence that excessive protease activity in the skin is an important factor in the development of atopic dermatitis. SRD44 is a topically formulated novel protease inhibitor that selectively inhibits Staphylococcal-derived aureolysin and matrix metalloproteinases (MMPs). Methods: This was a double-blind, vehicle-controlled randomized trial conducted in thirteen hospital dermatology outpatient clinics in Germany (9), Bulgaria (3) and Finland (1). Ninety-three out of 103 screened adult subjects with confirmed atopic dermatitis affecting ≤20% of body surface area, with an IGA score of 2 or 3 at randomization were randomized following a washout period to either SRD441 ointment or matching vehicle twice daily for 28 days. The primary efficacy endpoint was the clearance of Atopic dermatitis (AD score of 0 or 1 IGA) at Day 21. Secondary endpoints included measures of SCORing Atopic Dermatitis, pruritus self-assessment, rescue medication use and occurrence of new exacerbations. A range of safety and tolerance endpoints were included. Results: There were no significant treatment differences in IGA success rates at Day 21 (SRD441 ointment, 11.1%; vehicle ointment, 12.5%; P = 1.000). Evaluation of secondary efficacy variables revealed no clinical or important statistical differences between treatment groups. Eighteen subjects (19.4%) discontinued the study drug because of an AE (seven subjects [15.6%] in the SRD441 group and 11 subjects [22.9%] in the vehicle group). Twenty-seven subjects (60.0%) in the SRD441 group and 34 subjects (70.8%) in the vehicle group reported an adverse event (AE). Conclusions: SRD441 ointment did not demonstrate efficacy in the treatment of atopic dermatitis raising questions on the effectiveness of MMPs as a target for the treatment of atopic dermatitis. NCT00882245. [ABSTRACT FROM AUTHOR]

For more than five decades, topical corticosteroids and emollients have been the mainstay of therapy for atopic dermatitis. However, the potential for side-effects limits the clinical utility of corticosteroids in providing long-term disease control. With a unique mode of action that differs from that of corticosteroids, the steroid-free topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, provide skin-selective treatment that targets key factors involved in the pathogenesis of this chronic disease. An extensive series of clinical trials involving more than 16 000 patients with predominately moderate to severe atopic dermatitis in tacrolimus studies and over 2000 patients with primarily mild to moderate disease in pimecrolimus studies has shown that both TCIs provide effective and well-tolerated treatment for atopic dermatitis. Randomized controlled trials have demonstrated that tacrolimus is superior to conventional hydrocortisone-based regimens and does not cause skin atrophy or other steroidal side-effects. Both tacrolimus and pimecrolimus prevent disease flares and provide progressive and sustained disease improvement with long-term therapy. These and other clinical benefits of TCIs are discussed, together with the safety profiles of tacrolimus and pimecrolimus and their use in clinical practice. In addition, this review summarizes findings from the many trials carried out with these agents and outlines how TCIs can provide long-term treatment and control of a chronic skin disease that may persist for years. [ABSTRACT FROM AUTHOR]

Background Topical corticosteroids decrease collagen synthesis during short-term treatment and can induce skin atrophy when applied over the long term. (In contrast, short-term tacrolimus ointment therapy does not affect collagen synthesis. Objectives Our aim was to evaluate the long-term effects of 0.1% tacrolimus ointment on collagen synthesis and on skin thickness in adults with moderate to severe atopic dermatitis (AD) and to compare the findings with the effects of conventional steroid based therapy. Methods Fifty-six patients with AD were treated with 0.1% tacrolimus ointment in a 1-year, open label, prospective clinical trial. Thirty-six patients with AD applied conventional steroid-based therapy and 27 healthy subjects were recruited as controls. The primary endpoint was the change in levels of procollagen propeptides I and III measured by radioimmunoassay between baseline and month 12. Additional endpoints included the change in skin thickness measured by ultrasound between baseline and month 12. Results Procollagen propeptide baseline values were significantly lower in the group to be treated with tacrolimus ointment than in healthy controls. One-year treatment with tacrolimus ointment was associated with an increase in collagen synthesis: the median increase in combined procollagen propeptide levels was 272 µg L-1 (+ 140.9%, P < 0.001) and was accompanied by a significant increase in skin thickness. In three patients with visible skin atrophy, this condition ameliorated. Corticosteroid-based therapy had no significant effect on collagen synthesis; the median increase in combined procollagen propeptide levels was 11 µg L-1 (+ 3.9%). A significant reduction in skin thickness was demonstrated. Conclusions Long-term tacrolimus ointment therapy in patients with AD is nonatrophogenic and reverses corticosteroid-induced skin atrophy. [ABSTRACT FROM AUTHOR]

Topical corticosteroids are the usual treatment for atopic dermatitis (AD) in children but can have side-effects. This study compared the efficacy and safety of 0·03% tacrolimus ointment applied once or twice daily over a 3-week period with the twice daily application of 1% hydrocortisone acetate (HA) ointment in children with moderate to severe AD. Patients applied ointment daily to all affected body surface areas. The primary study endpoint was the percentage change in the modified Eczema Area and Severity Index (mEASI) between baseline and treatment end. Six hundred and twenty-four patients, aged 2–15 years, applied 0·03% tacrolimus ointment once daily ( n = 207), twice daily ( n = 210) or 1% HA twice daily ( n = 207). By the end of treatment, application of 0·03% tacrolimus ointment both once or twice daily resulted in significantly greater median percentage decreases in mEASI (66·7% and 76·7%, respectively) compared with 1% HA (47·6%; P < 0·001). Furthermore, the median percentage decrease in mEASI was significantly greater for patients applying 0·03% tacrolimus twice daily compared with once daily ( P = 0·007). Patients with severe AD benefited especially from twice daily application of 0·03% tacrolimus ointment compared with once daily application ( P = 0·001). Transient mild to moderate skin burning occurred significantly more often in the 0·03% tacrolimus groups ( P = 0·028) but resolved in most cases within 3–4 days. Laboratory parameters showed no clinically relevant changes. 0·03% tacrolimus ointment applied once or twice daily is significantly more efficacious than 1% HA in treating moderate–severe AD in children. Twice daily application of 0·03% tacrolimus ointment results in the greatest improvement in mEASI, and is especially effective in patients with severe baseline disease. [ABSTRACT FROM AUTHOR]

Tacrolimus ointment is the first of a new class of non-steroidal topical immunomodulators indicated for the treatment of atopic dermatitis. Topical tacrolimus has been subject to an extensive clinical development program involving more than 16,000 patients. A clinical trial program, including vehicle-controlled studies, short- and long-term comparative studies and long-term safety studies, has investigated tacrolimus 0.1% and 0.03% ointment for the treatment of atopic dermatitis in adults and children aged 24 months and older. Tacrolimus monotherapy is rapidly effective, resulting in clinical improvements within three days of starting therapy, and produces a progressive increase in efficacy that is sustained during long-term treatment. Tacrolimus treats the signs and symptoms of atopic dermatitis, reduces the incidence of flares, and offers the potential for long-term disease control. No major safety concerns have been reported to date. Tacrolimus ointment is generally well tolerated, the primary adverse events being mild to moderate and transient application-site reactions: skin burning, pruritus and erythema. Tacrolimus ointment is a significant advance in dermatology and provides physicians with an alternative to conventional topical corticosteroid therapy. [ABSTRACT FROM AUTHOR]

At present, the first-line drugs for treating atopic dermatitis are topical corticosteroids. They are effective when used short-term; however, long-term use of the corticosteroids is associated with suppressive effects on the connective tissue, seen as skin atrophy or resistance to therapy. Currently, two topical noncorticosteroid immunomodulators tacrolimus (FK506) and pimecrolimus (SDZ ASM 981) are under development, or already on the market in some countries for atopic dermatitis. These two compounds show structural similarity. In T lymphocytes they bind to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12. Tacrolimus shows a 3-fold greater affinity to FKBP compared with pimecrolimus. The tacrolimus/ pimecrolimus-FKBP complex further binds to calcineurin, an enzyme vital for the early activation of T cells. The consequence of calcineurin binding is a lack of activation of both T helper cell types 1 and 2. Further effects of these compounds have been suggested on other inflammatory cells, such as Langerhans cells and mast cells/basophils. In contrast to corticosteroids, no suppressive effects on connective tissue cells have been observed. Taken together, treatment of inflammation results in healing of the barrier function of the skin. This again results in reduced bioavailability of the drug, as compared with systemic use. Placebo-controlled studies have shown the efficacy of both tacrolimus (at 0.03 and 0.1%) and pimecrolimus (at 0.6 and 1%). The main adverse event in these studies has been a burning sensation and increased pruritus at the site of application. Typically, these adverse events are observed only during the first days of treatment. Long-term safety studies, of up to one year, have not revealed any new adverse events. So far, long-term use of topical noncorticosteroid compounds has not been associated with signs of immune deficiency. Although there is currently no evidence for clinically relevant, prolonged adverse effects, some of these, such as an increased risk of photocarcinogenesis, need to be monitored. There is evidence from tacrolimus studies that monotherapy results in better long-term results when compared with combination therapy with corticosteroids. Tacrolimus and pimecrolimus could replace topical corticosteroids as the first-line treatment of atopic dermatitis. [ABSTRACT FROM AUTHOR]

Previous studies have shown that IL-8 gene expression is enhanced by various stimuli, which induce different signal transduction pathways. A lipopolysaccharide (LPS)-induced pathway has been reported to be inhibited by glueocorticoids in monocytes. We have now examined the effect of dexamethasone on the LPS-induced and other signal transduction pathways leading to the production of IL-8 by human monocytes. Dexamethasone Inhibited the production of IL-8 stimulated with a cyclic adenosine motiophosphate analog or LPS. In contrast, dexamethasone had no significant effect on a phorbol ester (PMA)-stimulated IL-8 production. These results suggest that the signal transduction pathways leading to the production of IL-8 by human monocytes are differentially regulated by dexamethasone. [ABSTRACT FROM AUTHOR]

We showed earlier that most patients with contact dermatitis due to corticosteroids show cross-reactions when patch tested with hydrocortisone-17-butyrate (H-17-B). To test whether H-17-B could be used for detecting topical corticosteroid allergy, we screened patients undergoing routine patch testing with H-17-B. Patients with clearly allergic or doubtful/mildly irritant patch test reactions to H17-B, and with a history suggesting topical corticosteroid allergy, were further tested with a large panel of steroid preparations. 20 out of 4039 patients (0.5%) showed definite allergic test reactions to corticosteroids. A further 165 patients with clinically suspected corticosteroid allergy were directly tested with a panel of steroid preparations; 14 patients showed positive patch test reactions. Altogether, 33 out of 34 patients with corticosteroid allergy had positive test reactions to H-17-B. Inclusion of 1.0% H-17-B in ethanol in the standard patch test series improves the diagnosis of topical corticosteroid hypersensitivity. [ABSTRACT FROM AUTHOR]

The efficacy of cyclosporin (CyA) in the induction of remission in atopic dermatitis has been documented in controlled studies, However, little information is available on the duration of remission after CyA treatment. We studied the length of remission in 43 patients with severe atopic dermatitis after a 6-week treatment period with CyA at 5 mg/kg per day. After a follow-up of 6-26 weeks, depending on the time-point of relapse, a second treatment period with CyA, identical to the first, was performed. Disease activity was evaluated bi-weekly, using six different parameters: 1, a total body disease activity score; 2, the extent of the disease; 3, the occurrence of itch; 4, the occurrence of sleep disturbance; 5, the use of topical emollients; and 6, the use of topical hydrocortisone. A significant decrease in disease activity was observed. The total body disease activity score decreased from the baseline score of 31 to 116 at the end of the first part and to 134 at the end of the second part of the study. An almost maximal response to treatment was already apparent after 2 weeks of treatment. All the other efficacy parameters studied also showed a significant response to CyA treatment. A similar response to CyA was seen when the patients were re-treated. After both treatment periods, approximately half of the patients relapsed after 2 weeks (42% first part; 54% second part). After 6 weeks follow-up, the relapse rates were 71 and 90%, respectively. However, after the first treatment period five patients did not relapse during the 26-week follow-up period; the corresponding number was two after the second treatment period. The remission obtained in these seven patients was of clinical relevance, as their mean disease activity score at the end of the follow-up periods was only 28% (range 11-40) and 43% (both patients), respectively, of their own baseline score. In contrast with the rapid relapse of the dermatitis in the other patients after CyA was stopped, all disease parameters showed improvement when these patients were seen 1 year after the study, i.e. the mean activity score was 17.8 (58% of baseline). All seven patients who did not relapse after the first or second treatment period were still in remission after 1 year, and their mean activity score was only 32% (range 10-69) of their own baseline score. The most common side-effects were paraesthesiae and gastrointestinal discomfort. CyA dose was reduced in two patients because of drug-related side-effects; treatment was stopped prematurely in one patient. The present study confirms the efficacy of CyA in atopic dermatitis. It also suggests that CyA treatment may improve the long-term outcome of atopic dermatitis, although most patients initially relapsed a few weeks after CyA was stopped. [ABSTRACT FROM AUTHOR]

The efficacy of cyclosporin A (CyA) treatment was studied in seven patients with chronic dermatitis of the hands. CyA was started at a daily dose of 2.5 mg/kg in five patients, and 1.25 mg/kg in two patients. In patients who responded to the treatment at 2.5 mg/kg/day, the daily CyA dose was reduced stepwise, to the lowest maintenance dose of 1.25 mg/kg. In patients who did not respond, the dose was increased, to a maximum of 5 mg/kg/day. The patients were treated for 2–16 weeks. In six of the seven patients the dermatitis responded to CyA treatment within a few weeks. No response was seen with a starting dose of 1.25 mg/kg/day. In three of the five patients with a starting dose of 2.5 mg/kg/day, the daily CyA dose could be reduced to 1.25–2 mg/kg/day. After stopping CyA treatment, the dermatitis recurred during follow-up in three patients, three remained in remission, and one patient was not available for study. Treatment-related side-effects occurred in three patients, CyA treatment had to be stopped in one patient due to headache. The present study suggests that CyA could be a useful treatment for chronic dermatitis of the hands not responding to conventional therapy. [ABSTRACT FROM AUTHOR]

Data on the use of oral cyclosporin A (CyA Sandimmun®) therapy for severe adult atopic dermatitis have accumulated since 1987. Details of over 200 adult patients who have received short-term CyA were presented at an international workshop in April 1993, Eighty-six of these patients had participated In three randomized, double-blind, placebo-controlled studies in which CyA was given for 6–8 weeks. The efficacy and safety of short-term CyA treatment in atopic dermatitis is established, provided that appropriate guidelines are observed. Evidence to date suggests that atopic dermatitis patients are no more prone to toxicity than patients with psoriasis. In whom more detailed and longer- term data are available. Early data also suggest that long-term CyA may be effective in atopic dermatitis, but there is concern regarding long-term safety, as experience is still limited. Careful monitoring of all CyA-treated patients is therefore mandatory. CyA should only be used under the direct and regular supervision of a hospital-based dermatologist who is knowledgeable in the use of cyclosporin A. and experienced in the management of severe skin disease and in the use of potentially toxic drugs. [ABSTRACT FROM AUTHOR]

Interleukin 1 (IL-1) immunoreactivity in sebaceous glands was studied in paraffin sections of normal human skin. A panel of antibodies against IL-1α and β was tested using an immunoperoxidase labelling method. All the antibodies showed a similar specific labelling pattern: both glandular and ductal cells were immunoreactive for both IL-1α and β, provided optimal tissue fixation was used. [ABSTRACT FROM AUTHOR]

Corticosteroids suppress delayed-type hypersensitivity (DTH) reactions in vivo and impair lymphoid cell functions in vitro. In contact hypersensitivity (CHS) to corticosteroids, however, the corticosteroids are capable of inducing DTH responses in vivo. The present study examined the capacity of corticosteroids to induce in vitro proliferation of T lymphocytes from patients with CHS to corticosteroids. With peripheral blood mononuclear adherent cells as antigen-presenting cells (APC) and hydrocortisone-17-butyrate (H-17-B) as hapten, no proliferation responses were detected of T lymphocytes from patients with CHS to H-17-B. However, when epidermal Langerhans cells (LC) were used as APC, weak proliferation responses were observed. [ABSTRACT FROM AUTHOR]

Bouin-fixed paraffin sections or acetone-fixed cryostat sections were labelled with the avidin-biotin complex (ABC) or peroxidase-antiperoxidase (PAP) method using three monoclonal antibodies (MAbs) and two polyclonal antisera to human recombinant interleukin 1 beta (IL-1β) and three polyclonal antisera to human recombinant interleukin 1α (IL-1α). In the secretory coil both IL-α and β were detected in the clear, but not in the dark cells. Both luminal and basal cells of the coiled and straight ducts expressed IL-1α and β, the IL-1 labelling being more intense in the luminal cells. IL-1 was not usually detected in the initial portion of the intraepidermal eccrine sweat duct, whereas intense labelling was seen in the upper part including through the stratum corneum. In skin biopsies of the palm, taken after exercise, there was only faint IL-1 labelling of the secretory cells, whereas the luminal cells of the dermal ducts showed intense labelling for both IL-1α and β. In the acrosyringium, exercise did not alter the pattern for IL-1α and β, except that in the palm, some of the antibodies to IL-1β produced a more intense immunolabelling of the acrosyringeal cells. This study identifies a distinct and similar distribution of the two forms of IL-1 throughout the eccrine sweat-gland apparatus and indicates that part of the IL-1 epidermal pool originates from the sweat. [ABSTRACT FROM AUTHOR]

To determine whether topical provocation could be used for the diagnosis of fixed drug eruption (FDE) instead of systemic provocation, we applied the suspected drug at various concentrations (I-10%) in either petrolatum, 94% ethanol or dimethyl sulphoxide(DMSO)as an open test on both clinically normal skin and on previous FDE lesions in 24 patients with established FDE due to phenazone salicylate, a sulphonamide, doxycycline, trimethoprim, chlormezanone, a barbiturate, or carbamazepine. In 18 of the 24 patients, local provocation of FDE was seen at sites of previous eruption but never on clinically normal skin. With some drugs, e.g. phenazone salicylate, positive provocation of FDE was seen with all the vehicles used; with sulphamethoxazole and trimethoprim, a positive result was seen only in DMSO. To study cross-reactions to other phenazone derivatives in patients with an FDE caused by phenazone salicylate, we applied topical phenazone, aminophenazone and propyphenazone to sites of previous FDE lesions in three patients. In all three, a positive reaction was seen with phenazone, but only one patient showed positive results with aminophenazone and propyphenazone. The present study suggests that topical provocation is useful with several drugs causing FDE. Testing should always be performed on sites of previous FDE, and the sensitivity of the open topical testing can be increased in certain cases by using a vehicle which increases penetration of the drug. [ABSTRACT FROM AUTHOR]

To determine whether inhalant allergens could induce eczematous lesions we studied 17 patients with atopic eczema (with or without allergic rhinitis), 13 patients with allergic rhinitis without atopic eczema and 10 healthy control subjects. The allergens, birch pollen (Berula verrucosa) and house dust mite (Dermatophagoides pteronyssinus), were applied in aluminium chambers for 48 h on clinically normal skin. In 17 patients with atopic eczema, six epicutaneous test reactions of the delayed type to birch pollen and three to house dust mite were seen at 48 or 72 h. In 13 patients with allergic rhinitis without eczema there was one delayed reaction to birch pollen and none to house dust mite. No delayed type test reactions to either allergen were seen in the controls. Biopsies of the positive test sites revealed an eczematous reaction with epidermal spongiosis and microvesiculation. Immunostaining of cryostat sections showed dermal cell infiltrates consisting of mainly T lymphocytes (ratio of T4:T8, 2–6:1) and to a lesser degree Langerhans and indeterminate T6+ cells. 50-90% of the cells were Ia+. The numbers of basophils and mast cells did not exceed 10–15%. [ABSTRACT FROM AUTHOR]

Histochemical and immunohistochemical techniques were used to identify T lymphocytes, mononuclear phagocytes and plasma cells in situ from allergic and toxic epicutaneous test reactions. Intracellular α-naphthyl acetate esterase (ANAE), endogenous peroxidase and immunoglobulin were used as markers for inflammatory cells. In allergic contact dermatitis 761±7% of all cells were ANAE-positive T lymphocytes, 13±6% mononuclear phagocytes and 12±6% ANAE-negative cells. In toxic skin lesions the corresponding values were 64±20%, 18±15% and 18±6%,respectively. There were no statistically significant differences between the allergic and toxic skin reactions. The basic reaction type in allergic and toxic contact dermatitis seems to be similar, with possibly some qualitative and quantitative differences. [ABSTRACT FROM AUTHOR]

Skin lesions were produced by application of 50% potassium iodide to twelve patients with dermatitis herpetiformis (DH). Perivascular cellular infiltrates were found to be characteristic of developing lesions. The cells were mainly round cells; α-naphthyl acetate esterase staining revealed that in 24-h lesions the mean percentage of T-lymphocytes was 43%, that of mononuclear phagocytes 6% and that of non-T/non-M cells (mainly B-lymphocytes) 44%. The percentage of the latter was highest (mean 81%) in 6-h specimens, suggesting that these cells are participating in the early stages of lesion formation. The infiltrating cells in dermal papillae and within subepidermal vesicles were predominantly polymorphonuclear leukocytes (mean 86%) with some mononuclear phagocytes and non-T/non-M cells. Immunofluorescence examination confirmed that fibrin deposition is characteristic of the initial lesions of DH and showed that the same is true of fibronectin. Seven out of eight patients had fibronectin deposits in dermal papillae. IgA was found in all and C3 in most of the specimens and, with the exception of papillary vesicles and blister cavities, the intensity of IgA and C3 fluorescence showed no marked alterations during the development of lesions. [ABSTRACT FROM AUTHOR]