Ralf J. Ludwig

Psoriasis: a possible risk factor for development of coronary artery calcification.

Background  Psoriasis is a chronic inflammatory skin disorder affecting about 2% of white‐skinned individuals. Epidemiological data on the prevalence and degree of coronary artery calcification (CAC) as an indicator for cardiovascular diseases in patients with psoriasis are contradictory.

Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation

Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.

P-selectin: a common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis

P-selectin belongs to the family of selectin adhesion molecules, and is expressed by platelets and endothelial cells on stimulation. This pattern of expression may indicate an involvement of this molecule in inflammation and coagulation. Data from mice lacking P-selectin expression confirmed this assumption. In addition, a key role of P-selectin in the formation of tumour metastases has been established. Apparently unrelated, clinical experience has pointed towards a detrimental interaction of inflammation and cancer with thromboembolic diseases and vice versa. Therefore, targeting molecules such as P-selectin contributing to coagulation, inflammation and metastasis may offer novel therapeutic strategies to treat chronic inflammatory diseases and metastatic cancer. The authors aim to critically evaluate the contribution of P-selectin in these diseases, and discuss the value of therapeutic inhibition of P-selectin functions in coagulation, inflammation and metastasis.

Narrowband UVB and cream psoralen-UVA combination therapy for plaque-type psoriasis

BACKGROUND Psoralen-UVA (PUVA) and narrowband UVB (311-nm) therapy are considered to be first-line phototherapies for patients with moderate to severe psoriasis. To reduce side effects as a result of systemic resorption of psoralens, topical PUVA therapies have been developed and proven to be effective in the treatment of psoriasis. OBJECTIVE We sought to evaluate the combination therapy of narrowband UVB plus cream PUVA on selected psoriatic plaques compared with narrowband UVB or cream PUVA alone. METHODS A total of 30 patients (Psoriasis Area and Severity Index score of 8-15) were included in the randomized study. The combination therapy consisting of narrowband UVB whole-body irradiation followed by cream PUVA therapy for selected psoriatic plaques was evaluated in 10 patients with chronic plaque-stage psoriasis. For comparison, the therapeutic efficacy, number of treatments, and cumulative UV doses until remission (Psoriasis Area and Severity Index score < 4) of cream PUVA therapy or narrowband UVB alone was determined in 10 patients, respectively. RESULTS Both monotherapies induced clearance of psoriatic lesions in all patients within 5 to 7 weeks. Mean number of treatments for cream PUVA was 24 +/- 5; for narrowband UVB was 21 +/- 3. The mean cumulative UVA dose was 45.0 +/- 16.3 J/cm(2) and the mean cumulative UVB dose was 17.1 +/- 4.1 J/cm(2). Combination therapy resulted in complete clearance of lesions in all patients after 3 to 4 weeks. Mean number of treatment was 14 +/- 2, mean cumulative UVA dose was 18.7 +/- 4.7 J/cm(2), and mean cumulative UVB dose was 8.2 +/- 3.3 J/cm(2). The number of treatments (P <.001, analysis of variance), UVA dose (P <.001, t test), and UVB dose (P <.001, t test) were significantly reduced compared with both monotherapies. CONCLUSIONS Our results indicate that a combination therapy of narrowband UVB plus cream PUVA appears to have a significantly higher efficacy compared with either monotherapy. The cumulative UV doses were significantly lower in the combination therapy. We conclude that cream PUVA can be used in addition to narrowband UVB for areas that tend to clear less quickly than the rest of the body.

Heparin‐induced non‐necrotizing skin lesions: rarely associated with heparin‐induced thrombocytopenia

See also Warkentin TE, Linkins L‐A. Non‐necrotizing heparin‐induced skin lesions and the 4T’s score. This issue, pp 1483–.

Junctional adhesion molecule (JAM)‐B supports lymphocyte rolling and adhesion through interaction with α4β1 integrin

Junctional adhesion molecule‐A (JAM‐A), JAM‐B and JAM‐C have been implicated in leucocyte transmigration. As JAM‐B binds to very late activation antigen (VLA)‐4, a leucocyte integrin that contributes to rolling and firm adhesion of lymphocytes to endothelial cells through binding to vascular cell adhesion molecule (VCAM)‐1, we hypothesized that JAM‐B is also involved in leucocyte rolling and firm adhesion. To test this hypothesis, intravital microscopy of murine skin microvasculature was performed. Rolling interactions of murine leucocytes were significantly affected by blockade of JAM‐B [which reduced rolling interactions from 9·1 ± 2·6% to 3·2 ± 1·2% (mean ± standard deviation)]. To identify putative ligands, T lymphocytes were perfused over JAM‐B‐coated slides in a dynamic flow chamber system. JAM‐B‐dependent rolling and sticking interactions were observed at low shear stress [0·3 dyn/cm2: 220 ± 71 (mean ± standard deviation) versus 165 ± 88 rolling (P < 0·001; Mann–Whitney rank sum test) and 2·6 ± 1·3 versus 1·0 ± 0·7 sticking cells/mm2/min (P = 0·026; Mann–Whitney rank sum test) on JAM‐B‐ compared with baseline], but not at higher shear forces (1·0 dyn/cm2). As demonstrated by antibody blocking experiments, JAM‐B‐mediated rolling and sticking of T lymphocytes was dependent on α4 and β1 integrin, but not JAM‐C expression. To investigate whether JAM‐B‐mediated leucocyte–endothelium interactions are involved in a disease‐relevant in vivo model, adoptive transfer experiments in 2,4,‐dinitrofluorobenzene (DNFB)‐induced contact hypersensitivity reactions were performed in mice in the absence or in the presence of a function‐blocking JAM‐B antibody. In this model, JAM‐B blockade during the sensitization phase impaired the generation of the immune response to DNFB, which was assessed as the increase in ear swelling in untreated, DNFB‐challenged mice, by close to 40% [P = 0·037; analysis of variance (anova)]. Overall, JAM‐B appears to contribute to leucocyte extravasation by facilitating not only transmigration but also rolling and adhesion.

Management of cutaneous type IV hypersensitivity reactions induced by heparin

Localized hypersensitivity reactions to subcutaneous heparin injections have been described since 1952. Yet, the incidence of these reactions, which are distinct from skin lesions associated with heparin-induced thrombocytopenia type II (HIT II), remains uncertain. However, in the last 10 years an increasing number of patients have been reported, leading to the assumption that cutaneous hypersensitivity reactions towards heparin are underreported. Clinically patients present with itching, sometimes infiltrated, and blistering erythemas at the injection sites of heparins. The diagnosis of cutaneous heparin allergy may, on the one hand, lead to delay of required medical or surgical treatment. On the other hand, delayed initiation of treatment may lead to a generalized eczematous reaction. Hence, from review of 223 cases of patients with cutaneous hypersensitivity reactions to heparin, we here summarize the clinical picture of cutaneous type IV allergic reactions, define risk factors on both the patient- and drug-side, and give an overview of principle therapeutic alternatives, as well as recommendations for treatment options for emergency and elective patients. As the proposed management of patients with cutaneous hypersensitivity reactions to heparin may have fatal consequences when applied in patients with HIT type II, diagnosis of skin lesions in heparin-treated patients needs to be precise.

Experimental approaches to lymphocyte migration in dermatology in vitro and in vivo

Abstract:  Lymphocyte trafficking through the dermal compartment is part of the physiological surveillance process of the adaptive immune system. On the other hand, persistent or recurrent lymphocyte infiltrates are hallmarks of both types of chronic inflammatory skin diseases, Th1‐type such as psoriasis or Th2/allergic‐type like atopic dermatitis. A better understanding of the mechanisms underlying lymphocyte movements is one of the key prerequisites for developing more effective therapies. In this review, we introduce a range of simple‐to‐sophisticated experimental in vitro and in vivo approaches to analyze lymphocyte migration. These methods start from static in vitro adhesion and chemotaxis assays, include dynamic endothelial flow chamber, intravital dual photon, and transcutaneous live‐video microscopy, and finally encompass specific genetically deficient or engineered animal models. Discussing pros and cons of these assay systems hopefully generates both state‐of‐the‐art knowledge about the factors involved in most common chronic skin diseases as well as an improved understanding of the limitations and chances of new biologic pharmaceuticals that are currently introduced into clinical practice.

Platelet P-selectin reflects a state of cutaneous inflammation: possible application to monitor treatment efficacy in psoriasis.

Please cite this paper as: Platelet P‐selectin reflects a state of cutaneous inflammation: possible application to monitor treatment efficacy in psoriasis. Experimental Dermatology 2010; 19: 736–741.

PS3, A Semisynthetic β-1,3-Glucan Sulfate, Diminishes Contact Hypersensitivity Responses Through Inhibition of L-and P-Selectin Functions

Leukocyte extravasation is initiated by an interaction of selectin adhesion molecules and appropriate carbohydrate ligands. Targeting those interactions seems a promising approach to treat chronic inflammation. We developed a beta-1, 3-glucan sulfate (PS3) with inhibitory activity toward L and P-selectins under static conditions. Here, detailed investigation showed inhibition of P- and L-selectins, but not E-selectin under flow conditions (relative reduction of interaction with appropriate ligands to 34.4+/-16.6, 8.5+/-3.6, or 99.5+/-9.9%, respectively, by PS3 for P-, L- or E-selectin). Intravital microscopy revealed reduction of leukocyte rolling in skin microvasculature from 22.7+/-5.0 to 12.6+/-4.0% after injection of PS3. In the next experiments, mice were sensitized with 2,4,-dinitrofluorobenzene (DNFB), and lymphocytes were transferred into syngeneic recipients, which were challenged by DNFB. Inflammatory responses were reduced when immunity was generated in mice treated with PS3 or in L-selectin-deficient mice. No effect was observed when L-selectin-deficient donor mice were treated with PS3, further suggesting that PS3 acted primarily through inhibition of L-selectin. Elicitation of a contact hypersensitivity response was reduced in P-selectin-deficient and in PS3-treated mice. Again, PS3 had no effect in P-selectin-deficient mice. PS3 is a potent P- and L-selectin inhibitor that may add to the therapy of inflammatory diseases.