Integrative concepts of rosacea pathophysiology,clinical presentation and new therapeutics

Rosacea is a chronic relapsing inflammatory skin disease with high prevalence worldwide. Recent research suggests that dysregulation of innate and adaptive immune pathways as well as neurovascular changes is present, with different degrees of importance in the various subtypes. Neither the aetiology, genetics nor pathophysiological basis of the vascular, inflammatory or fibrotic changes is well understood. The clinical spectrum comprises a huge variability from erythema (vasodilation) to papules/pustules (inflammatory infiltrate) to phymata (fibrosis, glandular hyperplasia) making it a valuable human disease model to understand the interplay between the neurovascular and immune systems as well as the progression from chronic inflammation to fibrosis in skin. The lack of appropriate animal models emphasizes the importance of further translational research validating observed molecular pathways under disease conditions. A wide spectrum of physical (UV, temperature), biological (microbiota, food) and endogenous (genetic, stress) stimuli has been discussed as “trigger factors” of rosacea. Novel findings implicate keratinocytes, smooth muscle cells, endothelial cells, macrophages, mast cells, fibroblasts, Th1/Th17 cells, antibody‐producing B cells and neurons in the pathobiology of rosacea. So far, pattern recognition receptors like TLR2, transient receptor potential ion channels, cytokines, chemokines and proteases have been implicated as critical receptors/mediators. However, our understanding of the interactive networks on the molecular level is very limited. Identification of critical molecular components of the inflammatory cascade including antimicrobial peptides, the IL‐1β inflammasome, TNF, IFN‐γ, proteases and neuropeptides may provide the basis for novel pathomechanism‐based therapeutic approaches for this frequent and bothersome skin disease.     

Novel pharmacological approaches in the treatment of psoriasis

Progress in the understanding of psoriasis as a T-cell mediated inflammatory disease has led to the development of new immunomodulatory therapies. Currently the main focus is on the so-called biologics (or biological agents), including fusion proteins, monoclonal antibodies, cytokines and selective receptors. They mainly target single steps in the complex cascade of humoral and cellular inflammatory immuno-mechanisms that finally lead to the accelerated growth of epidermal and vascular cells in the psoriatic lesions. The most promising and advanced biological agents are discussed along with their influence on the critical pathophysiological steps in psoriasis, including depletion of T cells, blockade of initial T-cell activation and T-cell receptor (TCR) stimulation, blockade of costimulatory signals and T-cell proliferative signals as well as restoration of the T helper type 1 (Th1)/Th2 balance by diminishing type 1 cytokines and administration of type 2 cytokines. In addition to the biological agents, further development of 'classical' dermatological therapies, such as retinoids, or the discovery of new indications for non-dermatological agents contribute to the novel pharmacological approaches in the treatment of psoriasis.     

Psoriasis and occlusive vascular disease

To test the hypothesis that psoriasis is associated with an increased incidence of occlusive vascular disease (thrombophlebitis, myocardial infarction, pulmonary embolization, and cerebrovascular accident), the clinical records of 323 psoriatic and 325 non-psoriatic patients admitted to the dermatology service of the Roger Williams General Hospital were examined. The data obtained in this study suggest that (1) the occurrence rate of occlusive vascular disease is significantly greater in the psoriatic than in the non-psoriatic dermatological patient. This is particularly true in the male population; (2) psoriasis predisposes to occlusive vascular disease; and (3) the psoriatic patient with certain predisposing factors is at greater risk of experiencing an occlusive vascular episode than both the non-predisposed psoriatic and the non-psoriatic dermatological patient.     

What is the role of mitochondrial dysfunction in skin photoaging?

Skin ageing is a complex process involving both internal and external factors, which leads to a progressive loss of cutaneous function and structure. Solar radiation is the primary environmental factor implicated in the development of skin ageing, and the term photoaging describes the distinct clinical, histological and structural features of chronically sun‐exposed skin. The changes that accompany photoaging are undesirable for aesthetic reasons and can compromise the skin and make it more susceptible to a number of dermatological disorders. As a result, skin ageing is a topic that is of growing interest and concern to the general population, illustrated by the increased demand for effective interventions that can prevent or ameliorate the clinical changes associated with aged skin. In this viewpoint essay, we explore the role that mitochondria play in the process of skin photoaging. There is continuing evidence supporting the proposal that mitochondrial dysfunction and oxidative stress are important contributing factors in the development of skin photoaging. Further skin‐directed mitochondrial research is warranted to fully understand the impact of mitochondrial status and function in skin health. A greater understanding of the ageing process and the regulatory mechanisms involved could lead to the development of novel preventative interventions for skin ageing.     

Topical application of anti-angiogenic peptides based on pigment epithelium-derived factor can improve psoriasis

BackgroundPsoriasis is a common chronic inflammatory skin disorder with a high prevalence (3–5%) in the Caucasian population. Although the number of capillary vessels increases in psoriatic lesions, there have been few reports that have specifically examined the role of angiogenesis in psoriasis. Angiogenic factors, such as vascular endothelial growth factor (VEGF), may dominate the activity of anti-angiogenic factors and accelerate angiogenesis in psoriatic skin.ObjectiveWe investigated to identify small peptide mimetics of PEDF that might show anti-angiogenic potential for the topical treatment for psoriasis.MethodsWe examined the expression of PEDF in skin by immunohistochemical staining, immunoblotting, and RT-PCR. To identify potential PEDF peptides, we screened peptides derived from the proteolytic fragmentation of PEDF for their anti-proliferative action. Anti-psoriatic functions of these peptides were analyzed using a mouse graft model of psoriasis.ResultsThe specific low-molecular weight peptides (MW < 850 Da) penetrated the skin and showed significant anti-angiogenic activity in vitro. Topical application of these peptides in a severe combined immunodeficient mouse model of psoriatic disease led to reduced angiogenesis and epidermal thickness.ConclusionsThese data suggest that low-molecular PEDF peptides with anti-angiogenic activity may be a novel therapeutic strategy for psoriasis.     

Aktuelles Verständnis der Pathophysiologie der Rosazea

Rosacea is a chronic inflammatory skin disease mainly affecting the face. Four major clinical subtypes of rosacea can be identified: erythemato-telangiectatic, papulopustular, phymatous and ocular rosacea. Still, it is currently unclear whether these subtypes develop consecutively or if any subtypes may occur individually as part of a syndrome. Rosacea is characterized by facial flushing, erythema, chronic inflammation, edema and fibrosis. Several trigger factors can worsen the disease or cause recurring episodes of inflammation. Although some aspects in the pathophysiology of rosacea have been characterized in more detail during the past years, the precise interplay of the various dysregulated systems is still poorly understood. In early disease manifestations and milder stages, dysfunction of neurovascular regulation and the innate immune system seem to be driving forces in rosacea pathophysiology. A disturbed chemokine and cytokine network further contributes to disease progression. This current review highlights some of the recent findings in rosacea pathophysiology and points out novel targets for therapeutic intervention.     

Role of iron in dermatology

Iron is involved in several biological reactions and is essential to almost all forms of life. In contrast, iron is potentially toxic. It may participate in many dermatological disorders, including pigmentation changes, inflammation, porphyrias, infections and cancers. The involvement of iron in these disorders entails a variety of mechanisms, including among others simple deposition processes, activation or inactivation of enzymatic systems, impairment of phagocyte functions and interference with apoptosis. A better understanding of the role of iron might provide novel therapeutic strategies based on iron-chelating and/or anti-oxidant agents.     

Pemphigus and pemphigoids: Clinical presentation,diagnosis and therapy

Pemphigus and pemphigoid are two potentially life-threatening groups of autoimmune diseases, characterized by autoantibodies targeting structural components of desmosomes or hemidesmosomes, respectively. Affected patients typically show itchy/painful plaques or blistering skin lesions and/or impairing mucosal blistering and erosions, which may strongly impact their quality of life. Since the milestone work of Walter Lever in 1953, who differentiated these two groups of diseases by histopathological analysis of the level of antibody-mediated skin cleavage, enormous progresses occurred. Achievements made in laboratory diagnostics now allow to identify antigen specific structural proteins of the skin that are targeted by pathogenic autoantibodies. These progresses were accompanied by an increased understanding of the pathogenesis of these diseases thanks to the establishment of animal models reproducing disease and on studies on skin and blood of affected individuals, which have been leading to novel and disease-specific treatments. Yet, given their phenotypical overlap with more common dermatological diseases, correct diagnosis and appropriate treatment are often delayed, in some cases leading to irreversible sequelae, including organ dysfunction (i.e., loss of vision in mucous membrane pemphigoid). Here, we provide a concise overview of the clinical appearance, diagnosis and therapeutic management of pemphigus and pemphigoid diseases.     

Systemic Sclerosis: Current Concepts in Pathogenesis and Therapeutic Aspects of Dermatological Manifestations

Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease with protean clinical manifestations. Recent advances in understanding the pathogenic mechanisms have led to development of target-oriented and vasomodulatory drugs which play a pivotal role in treating various dermatological manifestations. An exhaustive literature search was done using Medline, Embase, and Cochrane library to review the recent concepts regarding pathogenesis and evidence-based treatment of salient dermatological manifestations. The concept of shared genetic risk factors for the development of autoimmune diseases is seen in SSc. It is divided into fibroproliferative and inflammatory groups based on genome-wide molecular profiling. Genetic, infectious, and environmental factors play a key role; vascular injury, fibrosis, and immune activation are the chief pathogenic factors. Vitamin D deficiency has been documented in SSc and correlates with the severity of skin involvement. Skin sclerosis, Raynaud''s phenomenon (RP) with digital vasculopathies, pigmentation, calcinosis, and leg ulcers affect the patient''s quality of life. Immunosuppressives, biologicals, and hematopoietic stem cell transplantation are efficacious in skin sclerosis. Endothelin A receptor antagonists, calcium-channel blockers, angiotensin receptor inhibitors, prostacyclin analogs, and phosphodiesterase type 5 (PDE-5) inhibitors are the mainstay in RP and digital vasculopathies. Pigmentation in SSc has been attributed to melanogenic potential of endothelin-1 (ET-1); the role of ET 1 antagonists and vitamin D analogs needs to be investigated. Sexual dysfunction in both male and female patients has been attributed to vasculopathy and fibrosis, wherein PDE-5 inhibitors are found to be useful. The future concepts of treating SSc may be based on the gene expression signature.     

Heat shock proteins and the skin

Heat shock proteins are of fundamental importance in cutaneous biology, from protection against UV-induced damage to wound healing and repair. Heat shock proteins have important regulatory roles in the control of apoptosis, regulation of steroid aporeceptors, kinases, and other protein remodelling events. They are also implicated in the control of cell growth, and as such, are potential targets for cancer diagnosis and treatment. Currently, emphasis is being placed on the potential use of these proteins in the prevention and treatment of disease. Therapeutic manipulation of these proteins may ultimately lead to novel treatments for diseases as diverse as melanoma to epidermolysis bullosa.     

To follow dermatological treatment regimens--patients' and providers' views

Adherence to long-term therapy for chronic illness is on average 50%. However, regarding adherence to dermatological treatment the existing literature is limited. The aim of the study was to acquire an understanding of issues associated with adherence to dermatological therapy. Focus group interviews were used in two types of fora: patients with chronic dermatological diseases and health care providers, including doctors, nurses and pharmacists working in dermatological care. Results reveal the providers' view of a suboptimal rate of adherence. According to both providers and patients, factors affecting adherence were patients' expectations and experiences of therapeutic effect, possibilities for the patient to take active part in treatment decisions, as well as mode of administration and type of medication. Suggested strategies for improvement are individualized patient education, continuous treatment support with assessment of medication-taking behaviour and enhanced communication skills among the providers.     

Vacation and tropical dermatoses

Besides fever and diarrhea, skin diseases are the third most common cause of morbidity in returning travelers after a stay in a tropical country. Approximately one- quarter of these dermatological symptoms can be referred to a classical tropical disease. The majority are of infectious origin. Often only the clinical appearance leads to the diagnosis of a tropical disease as myiasis, cutaneous larva migrans, tungiasis or cutaneous leishmaniasis. Not infrequently the dermatological symptoms lead to the diagnosis of a primarily systemic tropical disease. For example, an eschar with or without a rash might lead to the diagnosis of a South African tick bite fever caused by Rickettsia africae days before serology may turn positive. Less common tropical skin diseases such as lymphatic filariasis and loiasis need to be considered in returning long-term travelers and immigrants.     

Alopecia areata - animal models

Several rodent models with spontaneous and induced alopecia areata (AA), a nonscarring inflammatory hair loss disease with suspected autoimmune elements, have been identified. Of these, the C3H/HeJ mouse and DEBR rat have been most extensively used in examining AA development. Flow cytometry and micro array characterization, manipulation of inflammatory cells by in vivo cell depletion or cell receptor blockade, lymph node cell transfer between affected and unaffected rodents, and the recent use of transgenic knockout mice have given important insights into the development of AA. From our current understanding of rodent models, the development of AA relies upon a general genetic susceptibility where major susceptibility genes may be supplemented by minor disease severity modifying genes. However, the actual onset of AA, its duration, extent, and persistence in individual rodents may be modified by epigenetic factors. Rodent AA seems to be fundamentally, but not exclusively, Th1 cell mediated. Onset of disease may be dependent on several factors including the break down of the putative anagen stage hair follicle immune privilege, appropriate antigen presentation with costimulation of lymphocytes, presence of autoreactive lymphocytes, and a deficiency of functional immune system regulatory cells. Rodents have already been used in examining a variety of current AA treatments and developing new therapies with some success. With a greater understanding of AA disease mechanisms through rodent model research, improved and more specific treatment interventions may be defined.     

Current frontiers in systemic sclerosis pathogenesis

Systemic sclerosis is an autoimmune disease characterised by vascular dysfunction, impaired angiogenesis, inflammation and fibrosis. There is no currently accepted disease‐modifying treatment with only autologous stem cell transplant showing clinically meaningful benefit. The lack of treatment options reflects our lack of understanding of the precise molecular mechanisms occurring in the disease. Recent investigations have begun to decipher the molecular pathways underpinning the different aspects of the disease and may provide a rational clinical target(s). Uncovering the molecular mechanisms of the disease is important in understanding systemic sclerosis treatment. The aim of this review was to examine the current thinking in SSc pathogenesis and will offer novel areas for research which may yield novel therapeutics.     

Children with dermatological conditions admitted to paediatric intensive care: analysis of a national clinical audit database

There is little published literature about dermatological conditions in paediatric intensive care units (PICUs). The aim of this study was to describe the range of skin disorders in children admitted to PICUs in the UK and Ireland using data from a national audit. An analysis was conducted using data for 2002 – 2010 from the Paediatric Intensive Care Audit Network (PICANet). In total, 999 admissions of 882 children were identified, representing 0.8% of all PICU admissions. The most frequent dermatological conditions were skin infections, including cellulitis and necrotizing fasciitis, and inflammatory conditions. In 28% of cases, the dermatological diagnosis was considered the reason for PICU admission, in 35% it was a manifestation of systemic disease and in 37% it was considered incidental. Overall mortality was similar to the general PICU population, with 52 deaths (5.2%), but was greater in children with vascular/haematological conditions.     

Serum phosphate and chronic kidney and cardiovascular disease: Phosphorus potential implications in general population

It has already been established that in end-stage renal disease, hyperphosphatemia causes soft tissue calcification including vascular calcifications. It has also been supported that there is a connection between increased serum phosphate and morbidity in subjects, who suffer from renal disease. However, studies in these populations conferred mixed results. Several warnings are included in the role of serum phosphorus on cardiovascular disease in normal populations. Homeostasis of serum phosphate is obtained by the cooperation between regulatory hormones, cellular receptors and bone metabolic factors. There is the probability that one or more phosphate regulatory factors, rather than phosphate directly, may be responsible for observed associations with calcification and cardiovascular events in normal populations. Experimental studies have shown that the restriction of dietary phosphate prevents the progression of kidney dysfunction, although high dietary phosphate aggravates the renal function. In the current review, we discuss the role of serum phosphorus on progression of renal dysfunction and cardiovascular outcomes in chronic kidney disease patients and its involvement in important health risks in the general population.