Thomas A. Luger

International Consensus Conference on Atopic Dermatitis II (ICCAD II): clinical update and current treatment strategies

C . E L L I S * A N D T . L U G E R † O N B E H A L F O F T H E I C C A D I I F A C U L T Y : D . A B E C K , R . A L L E N , R . A . C . G R A H A M B R O W N , Y . D E P R O S T , L . F . E I C H E N F I E L D , C . F E R R A N D I Z , A . G I A N N E T T I , J . H A N I F I N , J . Y . M . K O O , D . L E U N G , C . L Y N D E , J . R I N G , R . R U I Z M A L D O N A D O A N D J H . S A U R A T

Neutral endopeptidase and angiotensin-converting enzyme: key enzymes terminating the action of neuroendocrine mediators

Abstract:  Zinc‐metalloproteases, such as neutral endopeptidase (NEP) and angiotensin‐converting enzyme (ACE), effectively control the bioavailability of peptide mediators released from sensory nerves, immune and skin cells during the cutaneous response to endogenous or exogenous noxious stimuli. Functional inactivation of NEP or ACE by transient inhibition or permanent genomic deletion results in a relative abundance of substance P (SP) and bradykinin (BK); this augments murine allergic contact dermatitis (ACD) by affecting ACD sensitization and elicitation, which involves neurokinin 1 receptors (NK1), BK receptors (B2) and an intact cutaneous sensory nervous system. Present evidence suggests that increased SP via NK1 is capable of boosting important functions of SP‐ and NK1‐expressing dendritic cells (DCs) and T cells (TCs) in an auto‐ or paracrine manner, which promotes ACD antigen sensitization. Moreover, skin inflammation or wounding in vivo, as well as treatment of epidermal and dermal cells by UV light and inflammatory mediators in vitro, regulates NEP and ACE expression and activity. Likewise, NEP and ACE are capable of processing neuroendocrine hormones, such as adrenocorticotropin and α‐melanocyte‐stimulating hormone. Thus, present data indicate that ACE and NEP, via proteolytic cleavage of peptide mediators and growth factors, represent important control factors for the inflammatory response in skin disorders such as psoriasis or allergic inflammation, but may also be capable of affecting pigmentation, cell survival, wound healing and tissue regeneration.

Pruritus – Pathophysiologie, Klinik und Therapie – Eine Übersicht

Pruritus ist eine unangenehme, selbständige Sinneswahrnehmung der Haut, die mit dem unstillbaren Verlangen einer mechanischen Reizbeantwortung einhergeht. Sie dient als physiologische Nozizeption dazu, schädigende Noxen wie Parasiten oder Pflanzenbestandteile von der Haut zu entfernen. Als Erkrankungssymptom vieler dermatologischer und systemischer Erkrankungen tritt Pruritus häufig in sehr quälender und therapierefraktärer Form auf. Chronischer Pruritus beeinträchtigt, ähnlich wie Schmerz, das Allgemeinbefinden des Patienten erheblich und kann im Extremfall zu physischer und psychischer Erschöpfung führen. Bis in die 90er Jahre des letzten Jahrhunderts existierte die theoretische Vorstellung, Pruritus sei ein unterschwelliger Schmerzreiz. Erst in den letzten Jahren konnte Pruritus als eigenständige, von Schmerz unabhängige Sinneswahrnehmung definiert werden mit eigenen Mediatoren, spinalen Reizleitungsbahnen und zerebralen Wahrnehmungsarealen. Diese Erkenntnisse führten zur Entwicklung neuer vielversprechender Therapien. In diesem Übersichtsartikel sollen Pathophysiologie, klinische Formen und Therapiansätze bei Pruritus dargestellt werden.

Efficacy and safety of intravenous immunoglobulin for immune-mediated skin disease: current view.

AbstractIntravenous immunoglobulins (IVIgs) exert a variety of immunomodulating activities and are, therefore, increasingly being used for the treatment of immune-mediated as well as autoimmune diseases. There is also accumulating evidence that high-dose IVIg (hdIVIg) is highly efficacious in the treatment of skin diseases, despite the lack of evide4nce from randomized, double-blind, placebo-controlled trials. A major advantage of hdIVIg in comparison with other commonly used immunomodulating therapeutic strategies is the excellent safety profile. Accordingly, IVIgs have been used successfully for the treatment of bullous autoimmune diseases such as pemphigus and bullous pemphigoid, dermatomyositis, scleroderma, cutaneous lupus erythematosus, toxic epidermal necrolysis, and erythema exudativum multiforme. In most cases, hdIVIg is effective only in combination with other immunomodulating strategies and allows for the reduction of adjuvants.Adverse effects of hdIVIg are generally mild and self-limiting. These include headache, myalgia, flush, fever, nausea or vomiting, chills, lower backache, changes in blood pressure, and tachycardia. To avoid infusion-related rigors, headaches, and other adverse events, pre-treatment with analgesics, NSAIDs, antihistamines, or low-dose intravenous corticosteroids may be beneficial. Controlled, double-blind, long-term clinical trials and a better understanding of the complex immunomodulating mechanism of IVIg are required to ultimately optimize dose, frequency, duration, and mode of IVIg administration.

Melanocortins in fibroblast biology – current update and future perspective for dermatology

Abstract:  The skin is a target organ and source for proopiomelanocortin (POMC)‐derived peptides, such as α‐melanocyte‐stimulating hormone (α‐MSH), which acts by binding to melanocortin receptors (MC‐Rs). Recent progress in our understanding of the cutaneous POMC system has demonstrated that human dermal fibroblasts (HDFs) are a novel target for α‐MSH. MC‐1R is expressed by HDFs in vitro and in situ. MC‐1R expression is also detectable in human connective tissue sheath fibroblasts (CTSFs) and in dermal papilla cells (DPCs) of the hair follicle, the latter concomitantly expressing MC‐1R and MC‐4R in vitro and in situ. Both HDFs and DPCs are capable of generating POMC‐derived peptides, although cell‐specific differences exist in the expression of prohormone convertases and the amounts of POMC‐derived peptides generated. Functional studies have shown that α‐MSH exerts anti‐inflammatory actions in human fibroblastic skin cells by suppressing interleukin‐1 (IL‐1)‐induced IL‐8 production, activation of the transcription factor activator protein‐1 (AP‐1) and induction of intercellular adhesion molecule‐1 by interferon‐α. In addition, α‐MSH antagonizes the effect of transforming growth factor‐β1 (TGF‐β1) on collagen synthesis in HDFs in vitro and exerts antifibrogenic activity in a mouse model of cutaneous fibrosis. These findings indicate that fibroblastic cells participate in the cutaneous POMC system in which α‐MSH appears to act as a modulator of inflammatory and fibrogenic responses. The biological activities of α‐MSH in fibroblastic cells of the skin point towards novel clues in our understanding of the pathophysiology of fibrotic skin disorders and inflammatory diseases of the hair follicle and, finally, suggest innovative therapeutic options for the treatment of these conditions.

The treatment of atopic dermatitis with topical immunomodulators

Atopic dermatitis (AD) is a common, chronic or chronically relapsing, inflammatory dermatosis that often presents in early childhood and may continue on into later life. Usually occurring in a personal or family setting of atopy, it is considered an immune–mediated condition with a predominance of CD4 LT2 helper lymphocytes, 3 hyperstimulatory highaffinity IgE receptor (FceRI)–expressing Langerhans cells, macrophages, and inflammatory dendritic epidermal cells, as well as effector cells such as eosinophils and mast cells. In addition, patients with AD have abnormal skin barrier function and epidermal lipid abnormalities. Much work has been done in the past 15 years on the pathophysiology of AD, and current thinking, based on analysis of circulating lymphocytes and immunohistochemical and in situ hybridization studies of lesional skin, favors a biphasic model of causation. The early immune response is considered to be a T-helper (Th2) cell 2 reaction, in which environmental antigens, such as food allergens and aeroallergens, but also perhaps autoantigens, play a crucial role. Moreover, superantigens, such as those from skin-colonizing staphylococci, can modulate this response. Recent work has suggested that immunomodulating cytokines such as interleukin (IL)-2, IL-4, and IL-15 and extracellular matrix components, including fibronectin and transferrin, may protect skin-infiltrating activated memory lymphocytes from apoptosis. Secretion by these T cells of interferon (IFN)in lesional skin causes upregulation of Fas protein (CD95) on keratinocytes, rendering them susceptible to apoptosis. Eczema might result from Fas ligand (FasL)–induced keratinocyte apoptosis. The Problem of Treatment

G‐DRG Version 2004: Veränderungen aus Sicht der Dermatologie

Die Finanzierung der stationären Krankenhausleistungen über ein DRG‐basiertes Vergütungssystem wird ab 2004 für alle Krankenhäuser verpflichtend eingeführt. Nachdem mit der Krankenhausfallpauschalenverordnung 2004 (KFPV 2004) die zentralen Punkte der G‐DRG‐Systemversion bekannt geworden sind, stellt sich die Frage nach den Konsequenzen. Festzustellen ist, daß der erste deutsche DRG‐Fallpauschalenkatalog sich sehr deutlich von dem bisherigen Optionskatalog unterscheidet, so daß eine intensive Auseinandersetzung mit den neuen Bedingungen erforderlich wird. Medizinökonomisches Handeln wird stärker als bisher den Krankenhausalltag prägen und Einfluß nehmen auf sich verändernde Versorgungsstrukturen. Die wesentlichen Grundlagen und die Anwendung der neuen Bestimmungen müssen deshalb bekannt sein. Neben den allgemeinen Abrechnungsregeln werden vor allem die Veränderungen im neuen Fallpauschalenkatalog erläutert und Auswirkungen für die Dermatologie beispielhaft beleuchtet. Weiterhin müssen die Klassifikationssysteme in den Versionen OPS‐301 SGB V und ICD‐10‐GM 2004 sowie die Deutschen Kodierrichtlinien Version 2004 Berücksichtigung finden. Daher werden ebenso die wesentlichen Neuerungen im Verwendungszusammenhang für die Dermatologie vorgestellt.