Hartwig Mensing

Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine

A randomized, double‐blind, multicentre study was performed to compare the efficacy of acitretin (50 mg/day) with hydroxychloroquine (400 mg/day) in 28 and 30 patients, respectively, suffering from cutaneous lupus erythematosus (LE). The study was carried out over an 8‐week period. Improvement of facial LE lesions after treatment with acitretin and hydroxychloroquine was assessed using several clinical parameters. In the acitretin group there was marked improvement or clearing of erythema in 10/24 patients (42%), of infiltration in 15/24(63%) and of scaling/hyperkeratosis in 12/20 (60%). In the hydroxychloroquine group there was complete clearing or marked improvement of erythema in 17/25 patients (68%), of infiltration in 17/25 (68%) and of scaling/hyperkeratosis in 15/23 (65%). Overall improvement occurred in 13/28 patients (46%) treated with acitretin and in 15/30 patients (50%) with hydroxychloroquine. The incidence of side‐effects was higher in the acitretin group, and necessitated discontinuation of treatment in four patients. The present results demonstrate that both acitretin and hydroxychloroquine provide effective treatment in approximately 50% of cases of cutaneous LE.

Effect of vitamin A and its derivatives on collagen production and chemotactic response of fibroblasts

Vitamin A and several other retinoids were added to fibroblast cultures in order to study possible alterations in biochemical properties and cellular responsiveness. The proliferation of cells was inhibited as the concentration of retinoids increased from 10‐9 to 10‐5mol/l. Synthesis of non‐collagenous proteins and production of both type I and type III collagen were decreased. The onset of type III collagen synthesis by tendon fibroblasts in culture was delayed. Furthermore, the chemotactic response of fibroblasts to fibroblast‐conditioned medium was markedly reduced in the presence of retinoids (10−6 to 10−12 mol/l).

Autoradiographic mapping of beta-adrenoceptors in human skin

A high density of β2-adrenoceptors has been found in human skin. Using autoradiographic mapping we investigated the distribution of β1- β2-receptors in normal and diseased human skin. Cryostat sections of human skin obtained at biopsy were incubated with [125I]-iodocyanopindolol and nonspecific binding was identified by incubation of adjacent sections with 200 μM (-)-isoproterenol; β2-receptors were visualized using CGP 20712A and β1-receptors using ICI 118,551 as competing agents. The epidermis was densely labelled with an even distribution throughout all layers. Most of the β-receptors were of the β2-subtype with practically no β1-receptors. β-Receptors were also localized to eccrine sweat glands, dermal blood vessels, and perivascular inflammatory cells, but there was no labelling of sebaceous glands. Topical glucocorticoids caused an increase in the density of epidermal β-receptors. We conclude that keratinocytes and eccrine sweat glands express high densities of β2-receptors suggesting that they may have a physiological role in the regulation of these cells.

Decline of Fibroblast Chemotaxis with Age of Donor and Cell Passage Number

Human dermal fibroblasts have a limited life span in culture, which is manifested by a progressive decline of their proliferative activity. Here we show by the Boyden Chamber assay that the chemotactic response of human fibroblasts to fibroblast-conditioned medium and fibronectin declines during cellular aging in vitro and in vivo. The chemotactic response of human embryonic fibroblasts (HEF) declined progressively after the 25th passage. Virtually no chemotactic activity could be observed after the 40th passage in culture. Fibroblasts cultures from donors aged between 70-90 years had lost chemotactic activity by the 15th passage. Cells from patients suffering from progeroid syndromes of premature aging showed, even in early passages, a very low chemotactic response (20% of the HEF) and lost their chemotactic activity after a few subcultures. The response to the chemoattractant fibronectin also decreased with aging. Immunofluorescence studies indicated that the decline in chemotactic activity was accompanied by the formation of a thicker fibronectin network in the extracellular matrix of senescent human fibroblasts and progeroid cells than that observed in early passage embryonic cultures. Since fibroblast chemotaxis and synthesis of connective tissue components probably play an important role in tissue repair, our results could contribute to an understanding of age-related differences in the healing of skin wounds.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis

Background Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. Objectives To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). Methods The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Results Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often ‘other antibodies’ (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. Conclusions These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

Β-Adrenergic receptors in psoriasis: evidence for down-regulation in lesional skin

Lesional psoriatic skin displays reduced responsiveness to Β-adrenergic stimulating agents. To elucidate whether the receptor protein itself is responsible for this, lesional and non-lesional psoritatic skin was investigated ex vivo for maximal Β-adrenergic binding density (Bmax) and Β-adrenergic binding affinity (KD). Epidermal crude membrane homogenates (ECMH) were prepared from split-thickness skin biopsies and saturated with the lipophilic Β-adrenergic antagonist (—)-125I-iodocyanopindolol (ICYP) as radioligand. Specific binding was saturable and Scatchard transformation of the binding data revealed a homogeneous class of Β-adrenergic receptors in all nine experiments. The maximal Β-adrenergic binding density was significantly less in lesional than in non-lesional psoriatic skin (Bmax=49.7 ± 7.2 fmol/mg protein vs. 67.1 ± 2.2 fmol/mg protein, n=9, P<0.05). The binding affinity was similar in lesional and in non-lesional skin (KD=9.0 ± 1.5 pmol/l vs. 8.0 ± 0.9 pmol/l). These results could at least partially explain the reduced responsiveness of the Β-adrenergic system in lesional psoriatic skin seen after stimulation with Β-adrenergic agonists.

High density of beta2-adrenoceptors in a human keratinocyte cell line with complete epidermal differentiation capacity (HaCaT)

SummaryA non-tumorigenic keratinocyte cell line with complete epidermal differentiation capacity (HaCaT) was used in radioligand binding experiments to determine the number of beta-adrenoceptors. Intact cells were saturated with 3H-labelled (−)CGP-12177 (CGP), a hydrophilic non-selective beta-adrenergic antagonist as radioligand. In order to investigate the beta-adrenergic subtype selectivity, displacement experiments were performed with different antagonists and agonists. Binding of CGP to keratinocytes has been shown to be reversible and saturable and to have high affintiy (Bmax=114.0±8.8 fmol/107 cells with 6866 receptors/cell, KD=0.095±0.017 nmol/l; n=11). Betaadrenergic antagonists inhibited binding yielding monophasic displacement curves. IC50-values (nmol/l) were: propranolol (non-selective) 1.68; CGP-12177 (non-selective) 1.08; ICI 118,551 (beta2-selective) 2.92; bisoprolol (beta1-selective) 1230; and CGP-20712 (beta1-selective) 24980. Agonists displaced CGP in the order isoprenaline> adrenaline>noradrenaline. We conclude that HaCaT cells express a high density of beta2-adrenoceptors providing a good model system to study adrenergic receptor mechanisms under reproducible experimental conditions in keratinocytes.

Clofazimine in dermatitis ulcerosa (pyoderma gangrenosum). Open clinical trial.

Five patients suffering from dermatitis ulcerosa (a variant of pyoderma gangrenosum) were treated with clofazimine in a daily dosage of 200 mg orally. Complete healing was noted in 2 patients, partial response in 2, no effect in 1. Side effects were mild and transitory in form of a red coloring of the skin (all patients) and mild ichthyosis (2 patients).

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients.

Objective. Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. Methods. The data of 3248 patients with SSc were analyzed. Results. Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. Conclusion. These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

Cutaneous metastases from carcinoma of the prostate

Cutaneous or subcutaneous metastases occur in 2% to 9% of visceral malignancies.lm4 Their occurrence is associated with advanced disease and poor prognosis. Skin metastases are seen most commonly from carcinomas of the breast, lungs, kidneys, stomach, uterus, and colon.5a6 Carcinomas of the prostate are common7 but account for less than 1% of all skin metastases.6 We describe a patient with carcinoma of the prostate and skin metastases.