Pustular diseases and keratinocyte-myeloid synergy.

Pustules are among the most common lesions produced in human skin. Infections by pathogens and drug-induced reactions are frequent causes of pustule formation. In recent years immune-mediated pustular diseases have drawn attention. It is proposed to classify pustular diseases according to the initiating events and sites: purely epidermal pustules, follicular pustules or pustules noted in autoinflammatory syndromes. The unifying pathology in all of the three categories is a microinvasion of activated neutrophils into epidermal or adnexal epithelia. Formation of pustules involves established IL-17 / IL-23, IL-36 / IL-36RN driven pathology, or IL-1 /caspase-activated autoinflammation. Pathophysiology demonstrates an intriguing synergy of keratinocytes with neutrophils. This is called keratinocyte-myeloid synergy (KMS). Non-infectious pustules are formed by IFNα controlling the production of chemoattractants (IL-8, LTB4) or induced by IL-1-regulated inflammasomes and caspase/ IFNß-induced chemotaxins. The presence of physical barriers, for example, cornified cell layers (str. corneum), is instrumental in establishing chemotactic gradients and blocking migrating neutrophils. In follicular KMS-driven pustular disorders, in contrast to epidermal pustules, neutrophil-mediated toxicity propagates lasting and expanding ulcerating diseases with increased levels of circulating immunoglobulin A (IgA). Complexed IgA is suggested to propagate ongoing pustular diseases. These are prerequisites essential for developing pustules in burdensome human skin diseases.

Severity, heterogeneity and systemic inflammation in psoriasis.

Psoriasis may express as active severe disease or as mild stable disease. In particular, patients with active severe disease present systemic involvement, including comorbidities and increased values of parameters reflecting an active state of innate immunity. In contrast, patients with mild stable disease show a dominancy of acquired immunity. In this review article, we report the clinical aspects of disease manifestations of both active and quiescent psoriasis as well as the immunological aspects, as well as the impact on antimicrobial resistance. The activity of psoriasis is not captured in the present outcome measures for severity assessment. The present review suggests that incorporating disease activity may be important in the assessment of the efficacy of treatments.

Bimodal immune activation in psoriasis.

Psoriasis is an immune-regulated skin disease with various clinical subtypes and disease activities. The majority of patients present with predominantly stable plaques. At the onset of new lesions, plaque-type psoriasis frequently demonstrates pin-sized and highly inflammatory papules sometimes with an inflammatory border. The histopathology of initial psoriasis differs from stable plaque-type psoriasis. Early lesions demonstrate innate immune cells with neutrophils, degranulating mast cells and macrophages. These are followed by interleukin (IL)-1-dependent T helper (Th)17 cells, finally resulting in the Th1-dominated immunopathology of stable plaque-type psoriasis, where mononuclear cells predominate with interspersed neutrophilic (Munro) microabscesses. These features suggest a bimodal immune pathway where alternate activation of either innate (autoinflammatory) or adaptive (autoimmune) immunity predominates. Neutrophilic infiltrations appear during early psoriasis with Munro abscesses. They are time limited and occur periodically, clinically best seen in linear nail pitting. These features strongly suggest a critical role for an IL-1-Th17-dominated autoinflammation in the initiation of psoriasis, followed by a Th1-dominated late-phase reaction. The concept of bimodal immune activation helps to explain results from therapeutic interventions that are variable and previously only partly understood.

Effectiveness of skin cancer screening programmes.

Skin cancer, nonmelanoma skin cancer (NMSC) and cutaneous malignant melanoma (CMM), is the most frequent cancer worldwide. It is amenable to early detection, and screening for skin cancer has the potential to reduce mortality and morbidity. However, there are no recommendations for population-based skin cancer screening programmes due to the lack of evidence for the effectiveness from epidemiological studies. In 2008 the first nationwide screening programme for NMSC and CMM in the world was established in Germany. The decision for implementing such a programme was based on the results and evidence of a pilot study that was conducted from 2003 to 2004. The pilot study revealed that a population-based screening programme for skin cancer is feasible and effective. Careful evaluation of the nationwide programme is crucial to generate strong evidence for long-term public health benefits.

Dermal fibroblasts from acute inflamed atopic dermatitis lesions display increased eotaxin/CCL11 responsiveness to interleukin-4 stimulation.

BACKGROUND: The presence of eosinophils and/or eosinophil-derived products in the dermis is characteristic for involved skin of patients with atopic dermatitis and contributes to the observed tissue injury. CCL11 is a potent chemoattractant and activator of human eosinophils and interleukin (IL)-4 is a potent inducer of CCL11 expression in dermal fibroblasts. OBJECTIVES: As increased fibroblast CCL11 expression may explain eosinophilic infiltration of involved skin areas in atopic dermatitis, we asked whether dermal fibroblasts from atopic patients differ from fibroblasts of healthy individuals in their ability to express CCL11. METHODS: We compared IL-4-induced CCL11 mRNA expression using reverse transcription-polymerase chain reaction from cultured dermal fibroblasts derived from biopsies of chronic lesional and acute lesional atopic skin as well as from skin biopsies derived from normal skin of healthy donors. RESULTS: Considerable variability in IL-4-induced relative CCL11 mRNA expression was detected in fibroblasts derived from biopsies of different individuals. The lowest median IL-4 concentration inducing half maximal CCL11 mRNA expression (EC(50)) was found in fibroblasts derived from acute inflamed atopic lesions. CONCLUSIONS: Inducibility of CCL11 in dermal fibroblasts upon stimulation with Th2 cytokines explains the tissue eosinophilia observed in the presence of Th2 cytokines and the localization of eosinophils to the dermis. Decreased EC(50) values of IL-4-induced CCL11 expression in fibroblasts from acute inflamed atopic skin lesions indicates increased IL-4 responsiveness in these lesions and further substantiates the special role for IL-4-induced dermal fibroblast CCL11 expression in acute lesions. Variable CCL11 expression in fibroblasts from different patients with atopic dermatitis indicates heterogeneity of factors determining atopic phenotype in atopic dermatitis.

The risk of psoriatic arthritis remains constant following initial diagnosis of psoriasis among patients seen in European dermatology clinics.

BACKGROUND: Estimates of psoriatic arthritis (PsA) prevalence among psoriasis patients vary widely (5-40%). The time to development of PsA in patients with plaque psoriasis also remains unclear. OBJECTIVES: To examine whether length of time since diagnosis of psoriasis affects risk of developing PsA, and to assess differences in quality of life (QoL), work-related issues, comorbidities and healthcare resource utilization (HCRU) for patients with PsA vs. psoriasis. METHODS: This large cross-sectional observational study was conducted in the UK, Italy, France, Spain and Germany in 2006. Dermatologists who actively treated patients with psoriasis recruited 10 consecutive patients with psoriasis. Presence of PsA, body surface area (BSA) affected with psoriasis and HCRU were recorded; patients completed EUROQoL (EQ5D) and employment disadvantages questionnaires. RESULTS: Patients with psoriasis (n = 1560) included 126 with PsA. Ninety per cent of these patients with PsA were seen by dermatologists who involved a rheumatologist in the care of their patients with PsA. Survival analysis indicated that the incidence of PsA among psoriasis patients remained constant (74 per 1000 person-years), while the prevalence increased with time since diagnosis of psoriasis, reaching 20.5% after 30 years. In addition, those with high BSA currently affected by psoriasis were more likely to have developed PsA (P < 0.028). PsA patients reported reduced QoL compared with psoriasis patients (EQ5D score: 0.56 vs. 0.82: P < 0.0005), as well as more work problems. PsA patients were more likely to be hospitalized (0.27 +/- 0.84 vs. 0.14 +/- 0.71 per year; P < 0.0005) and have additional comorbidities than those without PsA. CONCLUSIONS: The incidence of PsA was constant after initial diagnosis of psoriasis, leading to a higher prevalence of concomitant PsA over time. PsA is associated with decreased QoL and increased work-related problems, HCRU and comorbidities. Dermatologists should screen for PsA in their patients, especially long-standing patients who did not initially present with PsA.

Epidemiology and comorbidity of psoriasis in children.

BACKGROUND: Psoriasis is a common disease affecting all age groups. In contrast to adult psoriasis, only few studies on the epidemiology of childhood psoriasis have been published. OBJECTIVES: Assessment of prevalence and comorbidities of juvenile psoriasis in Germany based on health insurance data. METHODS: Data were collected from a database of about 1.3 million nonselected individuals from a German statutory health insurance organization which covers all geographical regions. Individuals with psoriasis were identified by ICD-10 codes applied to all outpatient and inpatient visits. The present analysis consists of all patients who were enlisted throughout the year 2005. The diagnosis of psoriasis was registered whenever there was at least one documented patient contact using code L40.* and subcodes. Comorbidities were also evaluated by ICD-10 diagnoses. RESULTS: In total, 33 981 patients with the diagnosis of psoriasis were identified. The prevalence in 2005 was 2.5%. The total rate of psoriasis in children younger than 18 years was 0.71%. The prevalence rates increased in an approximately linear manner from 0.12% at the age of 1 year to 1.2% at the age of 18 years. The overall rate of comorbidity in subjects with psoriasis aged under 20 years was twice as high as in subjects without psoriasis. Juvenile psoriasis was associated with increased rates of hyperlipidaemia, obesity, hypertension, diabetes mellitus, rheumatoid arthritis and Crohn disease. CONCLUSIONS: Psoriasis is a common disease in children. Like in adults, it is associated with significant comorbidity. Increased attention should be paid to the early detection and treatment of patients affected.

Explaining phenotype heterogeneity in patients with psoriasis.

Psoriasis is a heterogeneous disorder with many different phenotypes. Further, different forms may alter their morphology and course of disease in that, for instance, plaque-type psoriasis may become pustular and vice versa. With advancing insight in immunopathology phenotype switching can now be explained by directional changes from T cell-mediated pathology to an inflammatory neutrophilic pattern which is driven by innate signalling. Within this framework not a single 'antigen' but various causative agents play a key role.

Immune response profiles in human skin.

In addition to the function as a physical barrier human skin has been shown to be an important immune organ displaying various defense mechanisms, which can be divided into three major functional compartments: (i) Epithelial defense, which is characterized by antimicrobial peptides and proteins (AP) and which can be induced in inflammatory lesions but also in the absence of inflammation. (ii) Innate-inflammatory immunity, which involves recognition of microbial compounds by particular receptors like Toll-like receptors (TLR) and subsequent activation of signalling pathways resulting in expression of pro-inflammatory cytokines and interferons, as well as genes of adaptive immunity. Interferon alpha (IFNalpha) produced by plasmacytoid dendritic cells (DC) may stimulate myeloid DC to produce IL-12 resulting in classical T-cell activation or to produce IL-23 activating IL-17 producing T-cells (IL-23/IL-17 pathway). (iii) Adaptive immunity, which is based on antigen presenting cells, T-cells and B-cells and which is characterized by specificity and memory. In contrast to epithelial defense and innate-inflammatory immunity, adaptive immune functions provide slowly reacting protection. Recent improvements of our knowledge of dysregulated immune pathways associated with inflammatory skin diseases represent an important basis of novel immunomodulatory treatment modalities.

A classification of psoriasis vulgaris according to phenotype.

For nearly 200 years it has been appreciated that plaque psoriasis consists of a number of distinct clinical phenotypes. However, a reliable and simple stratification of clinical presentation of psoriasis is lacking. In the era of immunogenetic association studies and an advanced understanding of the pathomechanisms of psoriasis it is important that a classification of the disease according to phenotype is readily available. Such a classification would facilitate clinically relevant interpretation of investigational data. A meeting of the International Psoriasis Council produced a consensus on clinical phenotypes of psoriasis equally relevant to clinical practitioners and psoriasis researchers.

Prospective, randomized controlled trial on Lactobacillus rhamnosus in infants with moderate to severe atopic dermatitis.

BACKGROUND: A reduction of symptoms of atopic dermatitis (AD) in small infants by the administration of Lactobacillus rhamnosus has been reported in a few studies. One study with older children and adolescents failed to show any effect. OBJECTIVES: We conducted a prospective study to reassess the efficacy of orally administered L. rhamnosus strain GG (LGG) in infants with AD. METHODS: In a randomized, double-blind, placebo-controlled study, 54 infants aged 1-55 months with moderate to severe AD were randomized to daily 10 x 10(9) colony-forming units of LGG or to placebo during an 8-week intervention phase. Emollients, class I-II topical corticosteroids and antihistamines were permitted. RESULTS: The treatment with LGG was well tolerated. At the end of treatment there were no significant differences between the groups with respect to clinical symptoms (SCORAD, pruritus, sleep loss), the use of topical corticosteroids and antihistamines, immunological parameters, or health-related quality of life of the parents. CONCLUSIONS: Our results could not confirm LGG as an effective treatment of AD in infancy.

The unmet treatment need for moderate to severe psoriasis: results of a survey and chart review.

BACKGROUND: Conventional systemic therapies and phototherapy for psoriasis are limited by safety concerns that may preclude long-term treatment with these agents. OBJECTIVES: To estimate the unmet need for safe and effective treatments for psoriasis. METHODS: A survey was conducted at three psoriasis outpatient clinics in Europe. Male and female patients of any age with psoriasis requiring more than topical treatment were eligible to participate in the survey. Patient data were obtained from patients' answers to a questionnaire as well as by a chart review of each participating patient. The survey questionnaire addressed various aspects of psoriasis, including demographics and disease characteristics, treatment history, pre-existing medical conditions, and patient satisfaction with treatments received. RESULTS: A total of 301 patients participated in the survey, with approximately 100 patients from each centre. Nearly 90% of patients had received at least one systemic therapy or phototherapy for psoriasis, with 39% of patients receiving three or more. Ultraviolet B (UVB), methotrexate, psoralen plus ultraviolet A (PUVA), retinoids and cyclosporin were the most commonly used agents. Inadequate response, reported by patients as no change or worsening of disease with treatment, ranged from 10% to 50%. Contraindications to conventional systemic therapies were reported by 9-22% of patients. A substantial number of patients (42%) were not satisfied with these therapies. CONCLUSIONS: This survey highlights the unmet need for safe and effective therapies for moderate to severe psoriasis.

Low prevalence of the intrinsic form of atopic dermatitis among adult patients.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease commonly associated with respiratory allergies such as rhinitis and asthma, and a high serum level of IgE. In contrast to the 'classic' IgE-mediated allergic (extrinsic) form of AD, approximately 20% of the patients are reported to show normal IgE levels, lack of sensitizations towards environmental allergens, and absence of associated respiratory allergies. Accordingly, these patients are assigned to a nonallergic (intrinsic) form of the disease. OBJECTIVES: In order to define these two forms of AD more closely, 259 adult patients with AD were investigated. RESULTS: After a thorough diagnostic workup there were 18 patients (6.9%), who fulfilled the criteria of intrinsic AD. After follow-up, four additional patients had developed respiratory allergies or IgE-mediated sensitizations resulting in an overall proportion for intrinsic AD of 5.4%. CONCLUSIONS: Based on these figures the nature and relevance of the intrinsic form of AD deserves further evaluation.

Analysis of RUNX1 binding site and RAPTOR polymorphisms in psoriasis: no evidence for association despite adequate power and evidence for linkage.

BACKGROUND: A previous study identified two peaks of allelic association between psoriasis and single nucleotide polymorphisms (SNPs) mapping to distal chromosome 17q, including a disease associated SNP that leads to loss of a RUNX1 transcription factor binding site, and additional SNPs in the third intron of the RAPTOR gene. Another study found an association with SNPs in the RAPTOR gene, but not with the RUNX1 binding site polymorphism. METHODS: In an effort to confirm these observations, we genotyped 579 pedigrees containing 1285 affected individuals for three SNPs immediately flanking and including the RUNX1 binding site, and for three SNPs in the RAPTOR gene. RESULTS: Here we report further evidence for linkage to distal chromosome 17q, with a linkage peak mapping 1.7 cM distal to the RUNX1 binding site (logarithm of the odds 2.26 to 2.73, depending upon statistic used). However, we found no evidence for association to individual SNPs or haplotypes in either of the previously identified peaks of association. Power analysis demonstrated 80% power to detect significant association at genotype relative risks of 1.2 (additive and multiplicative models) to 1.5 (dominant and recessive models) for the RUNX1 binding site, and 1.3 to 1.4 for the RAPTOR locus under all models except dominant. CONCLUSIONS: Our data provide no support for the previously identified RUNX1 binding site or for the RAPTOR locus as genetic determinants of psoriasis, despite evidence for linkage of psoriasis to distal chromosome 17q.