Safety and efficacy of adapalene 0.1% / benzoyl peroxide 2.5% in the long-term treatment of predominantly moderate acne with or without concomitant medication - results from the non-interventional cohort study ELANG.

BACKGROUND: Acne is a chronic inflammatory disease requiring long-term treatment. The fixed-dose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-BPO) is indicated for the once-daily topical treatment of Acne vulgaris when comedones, papules and pustules are present. OBJECTIVE: The main objectives of this non-interventional study were to assess long-term efficacy and safety of adapalene-BPO in moderate to severe acne with and without concomitant medication. METHODS: Patients with moderate to severe acne received adapalene-BPO alone or in combination with concomitant medication over a course of 9 months. The primary efficacy endpoint was changes in acne severity according to the Leeds Revised Acne Grading System; secondary endpoints included treatment success assessed by the patient and safety. RESULTS: In total, 5131 patients were eligible for efficacy and 5141 for safety evaluation. The majority of patients (78.8%) received adapalene-BPO alone. About 21.2% received adapalene-BPO in combination with another agent, mostly topical antibiotics (8.8%) or systemic antibiotics (8.7%). Mean (±SD) acne severity improved from 5.6 ± 1.5 at baseline to 3.3 ± 1.9 at month 3, and further to 1.9 ± 1.9 at month 9 (both P < 0.0001). The degree of improvement correlated significantly with the severity at baseline. After 3 and 9 months of treatment, the facial skin was cleared completely (no more visible acne lesions) in 420 (8.2%) and 1326 patients (25.8%), respectively. A therapeutic effect was noted by the patients after a median time of 3 weeks (range: from 1 day to 12 weeks). No serious adverse events were reported. Facial skin irritations, mostly mild to moderate, occurred in 49.5% of patients and led to discontinuation in only 1.7% of cases. CONCLUSION: In consistence with previous clinical findings, the use of adapalene-BPO in daily practice routine is safe and effective in the long-term management of patients with moderate to severe acne.

Effect of adapalene 0.1%/benzoyl peroxide 2.5% topical gel on quality of life and treatment adherence during long-term application in patients with predominantly moderate acne with or without concomitant medication - additional results from the non-interventional cohort study ELANG.

BACKGROUND: In addition to physical long-lasting effects such as permanent scarring and disfigurement, acne has acute and long-term psychosocial effects that affect the individual's quality of life. As with other chronic diseases, treatment success is often compromised by poor adherence. OBJECTIVE: Two main objectives of this non-interventional study were to assess the long-term effect of the fixed-dose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-BPO gel) on quality of life and treatment adherence. METHODS: Patients with moderate to severe facial acne receiving adapalene-BPO alone or in combination with other drugs were enrolled in this non-interventional study. Data were documented at baseline and after 3 and 9 months of adapalene-BPO treatment. The secondary outcomes reported here include quality of life determined by the Cardiff Acne Disability Index (CADI), treatment adherence assessed by the ECOB (Elaboration d'un outil d'evaluation de l'observance des traitements medicamenteux) questionnaire, and patient satisfaction. RESULTS: In total, 5131 patients were included in the efficacy evaluation. After 9 months, mean (±SD) quality of life (CADI) improved significantly from 5.9 ± 3.0 to 2.4 ± 2.7 (P < 0.0001). Patients with more severe acne at baseline tended to achieve a greater improvement in quality of life. Long-term adherence was found to be good in 83.9% of patients. Adherence had a significant effect on efficacy and quality of life (P < 0.0001 respectively). The vast majority of patients (92.1%) reported subjective improvement at the interim analysis. Accordingly, most patients (84.8%) were satisfied or very satisfied with adapalene-BPO by the end of the observation period. CONCLUSION: The clinical improvement of the disease led to an increase in quality of life among acne patients. The treatment success may be a motivation factor for patients to stay adherent over the long-term treatment course, indicating the qualification of adapalene-BPO topical gel as an appropriate medication also in the long-term usage.

Treatment of therapy-refractive ulcera cruris of various origins with autologous keratinocytes in fibrin sealant.

BACKGROUND: Evaluation of the effects of cultivated, subconfluent, autologous keratinocytes in fibrin sealant (BioSeed-S) on the healing of therapy-refractive chronic wounds. PATIENTS AND METHODS: Open observational study in 60 patients with chronic leg ulcers and impaired wound healing of various origins. After whole-skin excision and cultivation of the autologous keratinocytes, the suspended cells were applied to the preconditioned wound in fibrin sealant. Wound epithelization and wound size were recorded at defined times. RESULTS: Fifty-two of the 60 participating patients could be evaluated. After 6 weeks, 29 ulcers (55.8%) were healed. The mean epithelization increased between the 8th and 42nd postoperative day from 23% to 62.5%. In 50.0% of the patients, global assessment of the wound showed a high degree of epithelization or healing after 42 days. In 32.6% of treated patients, improvement was observed, while no healing tendency was to be found in 17.4%. CONCLUSION: The present observational study indicates that the transplantation of autologous keratinocytes suspended in fibrin sealant could be of advantage in the treatment of refractive leg ulcers.

Modulation of urokinase-type and tissue-type plasminogen activator occurs at an early stage of progressing stages of chronic venous insufficiency.

Chronic venous insufficiency (CVI) progresses through a series of clinical stages, from healthy skin to poorly healing leg ulcers. The aim of this study was to analyse the distribution pattern and activity level of urokinase-type (uPA) and tissue-type plasminogen activators (tPA) in normal skin and in tissue biopsies of progressing stages of CVI, prior to and including venous ulceration. Biopsies 6 mm thick were taken from 14 healthy volunteers and 37 patients with 5 different stages of CVI: telangiectases; stasis dermatitis; hyperpigmentation; lipodermatosclerosis; and leg ulcer. Changes in the enzymatic activity and spatial localization of uPA and tPA during the progression of CVI were examined using in situ histological zymography. Normal skin and skin with telangiectases showed a punctate PA activity, consisting of both uPA and tPA activity. As CVI progressed, an increase in the distribution of uPA and a decrease in tPA activity was observed. The spatial localization of uPA was widespread within the dermis of biopsies from stasis dermatitis and lipodermatosclerosis and was associated in particular with the dermoepidermal junction. Hyperpigmented skin revealed a pattern of PA expression similar to that of healthy skin. However, leg ulcer specimens exhibited peak levels of uPA with little tPA. Furthermore, a plasminogen-independent protease activity that was not present in any of the earlier stages of CVI appeared. Our results indicate that there are profound changes in PA activity during the progression of CVI and that these changes begin early in CVI, for example, in stasis dermatitis. We hypothesize that the balance or imbalance of the PA activity in the later stages of CVI is an important pathogenic factor for the development of venous leg ulcer.

Skin surgery under local anesthesia leads to stress-induced alterations of psychological, physical, and immune functions.

BACKGROUND: Although excision of nevi under local anesthesia is a frequent and harmless operation, it apparently causes increased stress in many patients. However, thus far no studies have focused on the question of whether there are measurable effects on psychological, physiological, and immunological parameters. OBJECTIVE: To assess the perioperative stress reactions of patients undergoing skin surgery under local anesthesia for nevocellular nevi. METHODS: Fifty consecutive patients with pigmented nevi were examined at five points of measurement: 1 week and 30 minutes before the operation, during the operation, 30 minutes and 1 week after the operation. Somatic parameters included blood pressure, pulse, respiratory rate, and the level of pain. Lymphocyte subpopulations, white blood cell count, and cortisol in saliva were determined. Anxiety and general psychological distress were evaluated with validated questionnaires. RESULTS: There was a significant increase in anxiety at the time of surgery. In parallel, the physiological parameters as well as the CD56+ lymphocytes changed significantly. Preoperation anxiety and intraoperation pain were significantly higher in women (P <.001), but did not depend on age. CONCLUSION: There appears to be an interaction between physiological and emotional components in the operative stress reaction under local anesthesia. In patients with skin cancer, the perioperative stress may lead to transient impairment of immune function.

Expression of tissue-type and urokinase-type plasminogen activator activities in chronic venous leg ulcers.

BACKGROUND: Chronic wounds have been shown to exhibit elevated levels of several classes of proteinases. Plasminogen activators (PAs) are proteinases which play a major role in the biological processes involved in wound healing and abnormalities in PAs may play a role in the pathology associated with chronic wounds. Here, we investigated the expression of tPA and uPA activities in chronic venous ulcer biopsies. PATIENTS AND METHODS: In 22 patients with chronic venous leg ulcers, punch biopsies were taken from the ulcer base, ulcer margin and uninvolved skin from the thigh of the affected limb and PA activities were assessed using in situ histological zymography. RESULTS: tPA is the main PA activity in uninvolved skin but was reduced in ulcer margin skin and venous leg ulcer tissue compared to normal skin. uPA activity appeared throughout the ulcer margin skin but was at low levels in normal skin. Ulcer base tissue appeared to exhibit a plasminogen-independent proteinase activity not seen in normal or ulcer margin skin. CONCLUSION: PA activities are altered in and around chronic venous leg ulcers and their distribution suggests that blood vessels in CVI may be damaged and that the tissue is in an inflamed state.

Treatment of hyperkeratosis areolae mammae naeviformis with the carbon dioxide laser.

Hyperkeratosis of the nipple and areola is a rare mamma condition. Typical lesions are characterized by persistent verrucous thickening and dark pigmentation of the nipple or areola (or both) and may occur unilaterally or bilaterally in both sexes. We report what we believe to be the first therapeutic trial with carbon dioxide laser in a patient with hyperkeratosis areolae mammae naeviformis.

Expression of the adhesion molecules ICAM-1, VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic venous insufficiency.

In inflammation and wound healing, dynamic changes in cell adhesion and migration are fundamental properties of the cells involved. Disturbed interaction of leukocytes with microvascular endothelial cells has been proposed to be a central pathogenic factor in chronic venous insufficiency. This disease may therefore serve to elucidate dysregulated modulation of adhesion molecule expression in conditions of chronic inflammation and impaired wound healing. In this study, we determined how the expression of ICAM-1/VCAM-1 on endothelial cells and their ligands LFA-1/VLA-4 on leukocytes is modulated in skin of progressing stages of chronic venous insufficiency. Immunohistochemical staining of skin biopsies revealed an increase in the expression of ICAM-1 and VCAM-1 on endothelial cells in an early stage of venous disease such as stasis dermatitis. Such protein expression correlated with an increase of corresponding mRNA in skin biopsies. Expression of these CAMs on endothelial cells was accompanied by the occurrence of a marked perivascular infiltration of leukocytes, which expressed increased levels of LFA-1 and VLA-4. In progressing stages of chronic venous insufficiency, characterized by hyperpigmentation and lipodermatosclerosis, which precede skin ulceration, all these CAMs remained upregulated on endothelial cells and infiltrating leukocytes. Our findings indicate that following an initial peak expression during stasis dermatitis, vascular ICAM-1 and VCAM-1 expression is not downmodulated to baseline levels, but remains upregulated. This possibly promotes tissue damage by a perpetuated, upregulated influx of activated leukocytes, finally leading to skin ulceration.

[Coping with illness and quality of life of patients with port-wine stains treated with laser therapy]. / Krankheitsbewältigung und Lebensqualität bei Patienten mit Feuermalen unter Laser-Therapie.

Port wine stains (PWS) can lead to considerable emotional distress. The present study evaluated a) the coping with illness, the quality of life and the body image of patients with PWS and b) the effects of dye laser treatment on psychosocial parameters. Seventy PWS patients undergoing treatment with the flashlamp-pumped pulsed dye laser (FPDL) were assessed with questionnaires regarding coping with skin disease, quality of life and body image. Major clinical criterium was the lightening of PWS under treatment. PWS patients showed significant social phobia and avoidance similar to patient suffering from chronic skin diseases. The anxiety correlated with size and darkness of the PWS. In terms of helplessness and depressive mood, PWS patients were less affected than the comparison group. Also, PWS patients had reductions in quality of life and in body image. The coping strategies had a differential effect on the body image. Since there is a correlation between lightening of the PWS and reduction of emotional distress, FDPL therapy can be considered an effective treatment of PWS also in psychosocial terms.

[Hereditary benign telangiectasia: a rare form of primary telangiectasia with successful treatment with flash-lamp-pumped pulsed dye laser]. / Hereditäre benigne Teleangiektasien: Eine seltene Form primärer Teleangiektasien mit erfolgreicher Behandlung mit dem Blitz-lampen-gepumpten gepulsten Farbstofflaser.

We report about multiple cutaneous telangiectases occurring over 3 generations. The pattern of inheritance, the morphology of the lesions, and the absence of hemorrhagic episodes are consistent with an unusual variant of primary telangiectasia described as hereditary benign telangiectasia. Differential diagnosis and pathogenesis of this rare type of telangiectasia is discussed. The lesions have been treated with the flashlamp-pumped pulsed dye laser. The lesions were completely removed by two treatments. Six months later, the patient had no recurrence of the telangiectases. Without producing scars or permanent pigmentary changes a very good cosmetic result has been achieved and stigmatisation and psychic burden of this patient has been relieved.

Increased expression of platelet-derived growth factor receptor alpha and beta and vascular endothelial growth factor in the skin of patients with chronic venous insufficiency.

Growth factors produced by a variety of cells act as signalling peptides through specific cell surface receptor pathways. Functions such as cell proliferation, migration and differentiation have been assigned to each of them. Here, we report alterations of platelet-derived growth factor receptor alpha (PDGFR-alpha) and beta (PDGFR-beta) and vascular endothelial growth factor (VEGF) expression patterns in the progressive clinical stages of chronic venous insufficiency (CVI). A total of 30 punch biopsies were taken from patients with CVI, and VEGF and PDGFR were detected by indirect immunofluorescence and immunoperoxidase techniques. PDGFR-alpha and PDGFR-beta expression was strongly increased in endothelial cells of capillaries, pericapillary cells and connective tissue cells in the stroma of the skin of venous eczema and venous leg ulcer patients, and to a smaller extend in the dermis of those with lipodermatosclerosis. VEGF staining showed a similar expression pattern in the progressive CVI stages. However, staining of vessels in particular might simply reflect binding of VEGF, secreted by keratinocytes or fibroblasts, to its receptors. Growth factor and receptor expression in specimens from telangiectases and reticular veins, and from pigmented areas, resembled that of normal skin. We conclude that PDGFR-alpha, PDGFR-beta and VEGF play an important role in mediating inflammation and epithelial hyperproliferation in venous eczema, inducing connective tissue sclerosis in lipodermatosclerosis, and causing the reduced reepithelialization tendency in venous ulcers. We speculate that endothelial proliferation with chronic venous hypertension might be mediated by these growth factors.

Patterns of epidermal growth factor receptor, basic fibroblast growth factor and transforming growth factor-beta3 expression in skin with chronic venous insufficiency.

Growth factors which act as signalling peptides through specific cell surface receptors are involved in functions such as cell proliferation, migration, and differentiation. Here, we report on alterations of the epidermal growth factor receptor (EGFR), basic fibroblast growth factor (bFGF) and transforming growth factor beta3 (TGF-beta3) expression patterns in the skin at various stages of chronic venous insufficiency (CVI). Thirty punch biopsies were taken from patients with CVI and growth factors or the growth factor receptor were detected by indirect immunofluorescence and immunoperoxidase techniques. EGFR, bFGF, and TGF-beta3 expression is strongly increased in the stroma of venous eczema and in leg ulcer skin, and to a lesser extent in the dermis of patients with lipodermatosclerosis. Venous eczema and lipodermatosclerosis epidermis show an elevated EGFR and bFGF synthesis throughout all strata. In the different CVI stages, telangiectases and reticular veins and pigmentation EGFR and bFGF staining are limited to the basal layer. We conclude that the alterations in the expression of EGFR, bFGF and TGF-beta3 precede changes in the affected skin within progressing stages of CVI. The exact mechanisms of growth factor involvement in the pathogenesis of venous ulceration remain to be resolved.

Possible role of coagulation factor XIII in the pathogenesis of venous leg ulcers.

BACKGROUND: Aim of this placebo-controlled clinical study was to examine the expression pattern of coagulation factor XIIIa in patients with chronic venous leg ulcers and the impact of a 10 day topical factor XIII treatment on ulcer healing, leg ulcer size and radius reduction. PATIENTS AND METHODS: 24 patients were stratified into two groups, each consisting of 12 patients, with leg ulcers > 1.000 mm2, or < 1.000 mm2. Four patients of each study group were assigned to the control group (n = 8). All leg ulcers were treated by topical application of non-adhering dressings and compression therapy. Patients of the treatment group (n = 16) were treated by additional topical treatment off factor XIII twice daily for ten days. Immunohistochemical staining of leg ulcer specimens before and after treatment (day 10) was performed in all patients. RESULTS: The immunohistochemical staining of factor XIIIa in all specimens before and after therapy showed no significant increase in the expression of factor XIIIa. Comparison of the leg ulcer size, radius and daily radius reduction in the treatment and control group showed no significant differences in values of patients with leg ulcers > 1.000 mm2. However, a decreased leg ulcer size and radius was found in patients of the treatment group with more acute leg ulcers < 1.000 mm2 in contrast to patients with larger leg ulcers (daily ulcer radius reduction from day 0-10; 0.31 mm versus 0.13 mm, p < 0.015). CONCLUSIONS: These results indicate that locally applied factor XIII promotes especially wound healing of more acute smaller venous leg ulcers. Since immunohistochemical staining of factor XIIIa showed no significant differences before and after therapy, we propose that factor XIII is inactivated rapidly after local application on venous leg ulcers.

Psychosocial stress of patients with port wine stains and expectations of dye laser treatment.

BACKGROUND: Port wine stains can be treated successfully with the dye laser in most cases. The indication for treatment is made on the basis of the emotional stress arising from the port wine stain. Studies of the extent of psychosocial stress to date have led to contradictory results. OBJECTIVE: To address the question how many patients with port wine stain suffer psychosocial stress and how this group can further be characterized. Moreover, the specific expectations of treatment were to be elucidated. METHODS: During dye laser treatment, 76 patients with port wine stains were evaluated by questionnaires regarding (a) emotional well-being, (b) quality of life, (c) body perception and (d) disease-specific stress and expectations of therapy. RESULTS: Patients with port wine stains showed significantly higher emotional stress than healthy controls. They were particularly impaired in quality of life with respect to their social life and felt less attractive than a healthy control group. Patients with high emotional stress placed high hopes on the laser therapy with regard to chances of employment and social contacts. CONCLUSION: The data point to the need for thorough patient consultation prior to laser therapy in order to avoid excessive expectations. Psychological consultation is recommended for emotionally labile PWS patients.

Development and validation of a disease-specific questionnaire on the quality of life of patients with chronic venous insufficiency.

BACKGROUND: Recording of Quality of Life (QoL) is taking on increasing importance in medicine. Although QoL cannot be measured directly, numerous methods studies have demonstrated that important areas of QoL can be addressed by validated questionnaires. The present study was designed to examine a new disease-specific, German-language questionnaire, the Freiburger Questionnaire of QoL in venous diseases (FLQA), with respect to reliability, validity and patient acceptance-among patients with chronic venous insufficiency (CVI). PATIENTS AND METHODS: The FLQA consists of 83 items and differentiates between limitations in QoL in 7 scales: physical complaints, everyday life, social life, emotional status, therapy, satisfaction, occupation. Data were collected from 246 patients with CVI stage I (n = 107), II (n = 75) and III (venous ulcer, n = 64) in the Widmer classification. RESULTS: In the psychometric test, the majority of scales showed little or no top or bottom effect. The internal consistency of the scales was generally high (Cronbach's Alpha in all scales more than alpha = .70 and in 4 scales above alpha = .90). The convergent validity with the Nottingham Health Profile and the ALLTAG was high in several scales. The FLQA showed good discriminant validity and significantly differentiated between the clinical CVI stages in several areas of QoL. The change sensitivity during the course of therapy was also good. In a feasibility test, the acceptance values among patients were high with respect to ease of understanding and description of the QoL areas relevant to them. The mean time to fill out the questionnaire was 21 +/- 6 minutes. CONCLUSION: Overall, the FLQA appears suitable to reliably record characteristics of QoL in patients with CVI in both course and cross-sectional studies.

Low-frequency ultrasound treatment of chronic venous leg ulcers in an outpatient therapy.

Low-dose ultrasound seems to be an effective method to enhance wound healing, particularly in chronic venous leg ulcers. The aim of our investigation was to examine the effect of 30 kHz low-dose ultrasound in local treatment of chronic venous leg ulcers, when added to conventional therapy of outpatients. Twenty-four patients with chronic ulcerations of the leg due to chronic venous insufficiency were randomised in placebo-controlled parallel groups in a single-blind clinical study. Patients were randomised to conventional therapy with topical application of hydrocolloid dressings and compression therapy or conventional therapy with additional ultrasound treatment for 12 weeks. The ultrasound treatment consisted of 10 min of footbathing, with application of 30 kHz continuous ultrasound 100 mW/cm2 three times a week. The ulcer area was measured by planimetry, using a millimeter grid before treatment and after 2, 4, 6, 8, 10 and 12 weeks of therapy. The ulcer radius and the daily ulcer radius reduction were calculated. Colour photographs of the ulcers were taken under standard conditions at the same time. After each treatment local findings and side effects were recorded. After 12 weeks of treatment the control group showed a mean decrease of 16.5% in the ulcerated area. In contrast the mean ulcerated area decreased by 55.4% in the ultrasound group (p<0.007). The daily ulcer reduction in the ultrasound-treated patients was 0.08 mm+/-0.04 mm and in the placebo patients 0.03 mm+/-0.03 mm. Patients recorded only minor side-effects such as a tingling feeling and occasionally pinhead-sized bleeding in the ulcer area. The application of low-frequency and low-dose ultrasound is a helpful treatment option in chronic venous leg ulcers, especially if they do not respond to conventional ulcer treatment.

Changes of cytokeratin expression in the epidermis with chronic venous insufficiency.

BACKGROUND: A specific, individual pattern of cytokeratins (Cks) is expressed by each epithelial cells as part of the cytoskeleton. Cks are established as markers of epidermal differentiation. Basal cells are characterized by CK5 and 14 expression, whereas CK 1, 10 and 11 are typical for the suprabasal compartment of normal epidermis. Here, we investigated changes of Pan-CK, CK 10, and CK 14 expression in the epidermis in various stages of chronic venous insufficiency (CVI). PATIENTS AND METHODS: In punch biopsies of 24 patients with chronic venous insufficiency and of 6 volunteers with normal skin Cks were detected by indirect immunofluorescence using monoclonal antibodies against CK 10, CK 14 and Pan-CK. RESULTS: CK 10 and Pan-CK staining intensity increased with the severity of CVI changes. Suprabasal cells showed an upregulation of CK 10 and Pan-CK expression first in venous eczema. CK 14 expression is under normal condition confined to the basal cell layer of the epidermis. However in venous eczema and lipodermatosclerosis, CK 14 is detected in the suprabasal epidermal compartment. CONCLUSIONS: It is therefore concluded that altered differentiation and stratification mechanisms occur in keratinocytes in the epidermis with CVI first detectable in the stage of venous eczema. These changes are accompanied by a characteristic CK expression pattern.

Clinical histochemical and immunohistochemical investigation of the capillary basal membrane in chronic venous insufficiency.

Present investigations regarding the pathogenesis of chronic venous insufficiency (CVI) are focusing on microvascular changes. The aim of our investigation was to examine the correlation between the thickness of pericapillary type IV collagen depositions, basal membrane alterations and transcutaneous oxygen tension (TcPO2) in CVI-patients. Histochemical and immunohistochemical investigation of the capillary basal membrane was performed on 15 biopsies from normal controls, as well as 30 patients with CVI stage I and III (classification by Widmer & Stähelin). In all subjects TcPO2 was measured just prior to biopsy procedures in exactly the same area where the specimen was subsequently excised. The microscopically measured thickness of the collagen IV layer and the basal membrane was increased significantly in patients with CVI. Specimens from normal controls showed a collagen IV layer thinner than 0.1 micron. Patients with CVI stage III revealed strong collagen IV depositions between 0.2 and 0.3 microns. Comparison between TcPO2 and histological findings in the measured ares showed oxygen pressure varying from 62 mmHg (SEM 4.94 mmHg) in normal controls, down to 13 mmHg (SEM 3.39 mmHg) in patients with thick collagen IV layers. Besides an increased collagen IV layer, microvascular thrombosis and a thickened basal membrane have to be considered for impaired capillary perfusion.