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Biomedical subjects

Enno Christophers

Publications and source records attributed to Enno Christophers.

At least 19 recordsLinked to original sources
PubMed2006

Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis.

The role of chronic inflammation causing metabolic and vascular disorders is increasingly recognized. It is hypothesized that proinflammatory cytokines contribute to atherogenesis, peripheral insulin resistance, and the development of hypertension and type II diabetes. Psoriasis as a chronic inflammatory skin disorder is characterized by a variety of immunologic and inflammatory changes and may similarly predispose for those disorders. The objective of this study was to elucidate the association of psoriasis with chronic vascular and metabolic disorders. We investigated a total of 581 adult patients hospitalised for plaque type psoriasis as compared to 1,044 hospital-based controls. A distinct pattern of chronic disorders was found to be significantly associated with psoriasis, including diabetes mellitus type II [odds ratio (OR)=2.48], arterial hypertension (OR = 3.27), hyperlipidemia (OR = 2.09), and coronary heart disease (OR = 1.95). The combined presence of these conditions together with obesity, known as the metabolic syndrome, was clearly more prevalent in psoriasis patients (OR = 5.29). In addition, psoriasis patients were significantly more likely to be smokers (OR = 2.96) and to have a regular or heavy consumption of alcohol (OR = 3.33 and 3.61, respectively). In conclusion, psoriasis patients appear to be at higher risk for diabetes mellitus and cardiovascular disease. This could likely be due to the effects of chronic inflammatory changes, in particular the secretion of proinflammatory cytokines. The risk of late term cardiovascular complications might support the use of systemic treatment in psoriasis.

Adolescent↗
PubMed2006

Novel anti-inflammatory properties of the angiogenesis inhibitor vasostatin.

Endothelial cells are critically involved in the pathogenesis of inflammation, which is characterized by vasopermeability, plasma leakage, leukocyte recruitment, and neovascularization. Therefore, inhibitors of endothelial cell function could reduce inflammation. In this study, we evaluated the effects of the angiogenesis inhibitor vasostatin on inflammations induced by contact hypersensitivity reactions in mouse ears. Vasostatin-treated mice revealed significantly reduced edema formation, resulting from lower plasma leakage and inhibition of inflammation-associated vascular remodeling. Intravital microscopy studies of inflamed ears showed a decrease in the fraction of rolling leukocytes in vasostatin-treated mice, and Lycopersicon esculentum lectin-perfused ears revealed fewer leukocytes adherent to the vessel wall. The inflammatory infiltrate from vasostatin-treated mice was characterized by fewer CD8+ T cells, neutrophils, and macrophages compared to the saline-treated animals. In a modified Miles assay, vasostatin inhibited vascular endothelial growth factor-A-induced permeability, and inflamed ear tissues from vasostatin-treated mice expressed significantly reduced levels of the vascular destabilizer angiopoietin-2. These results reveal a previously unrecognized anti-inflammatory property of the angiogenesis inhibitor vasostatin, and suggest that vasostatin is a potential candidate drug for the treatment of inflammation.

Angiogenesis Inhibitors↗
PubMed2006

Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.

Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.

Adult↗
PubMed2006

CARD15 mutations in patients with plaque-type psoriasis and psoriatic arthritis: lack of association.

Psoriasis has a strong genetic component in the development of the disease as indicated by familial occurrence and a high concordance rate among monozygotic twins. In genome-wide scans for psoriasis several susceptibility loci have been detected, but the disease-causing genes have not yet been identified. A recent scan, performed on psoriatic arthritis (PsA), which occurs in about 15% of the psoriasis patients showed a significant locus on chromosome 16 in a region that was already described by genome scan for psoriasis. CARD15, a major susceptibility gene for Crohn's disease (CD) on chromosome 16q, is an interesting candidate gene for psoriasis, because there is a documented clinical association of CD with psoriasis, and recently the association of CARD15 mutations with PsA was reported in Newfoundland population. We investigated the association of this variant with PsA and the overall psoriasis genotype in 59 independent patients with PsA in comparison with 361 age and sex-matched controls. In addition, a second cohort of 89 independent North American PsA patients was included. The diagnosis of psoriasis was made by a dermatologist based on standard clinical criteria. In these patients, PsA was defined as an inflammatory joint disease, negative rheumatoid factor, and lack of another causative condition for arthritis. Using case-control analysis, the G908R mutation was weakly associated with psoriasis and PsA, but due to the low frequency of this mutation statistical significance was not reached. All other variants including leu1007fsinsC and R702W did not show any association with psoriasis or PsA. In conclusion, a disease-causing role for CARD15 mutations could not be confirmed in German or American subjects with PsA.

Arthritis, Psoriatic↗
PubMed2005

Halo dermatitis followed by the development of vitiligo associated with Sutton's nevi.

Halo dermatitis (Meyerson's nevus) is an inflammatory, sometimes itchy, eczematous eruption usually encircling a preexisting melanocytic nevus that can be mistaken for malignant melanoma or Sutton's nevus. Unlike the latter, it mostly resolves spontaneously within weeks and never causes regression of the central lesion. Sutton's nevi, however, are frequently found in otherwise healthy individuals and patients suffering from vitiligo or malignant melanoma. The simultaneous appearance of Sutton's nevus and halo dermatitis has been reported before. However, the causes of both diseases remain unclear. We report a 16-year-old female who developed vitiligo and Sutton's nevi 6 months after a halo dermatitis lesion was excised. The coincidence of these disorders suggests common or similar immunological mechanisms induced by pigment cells and/or their components.

Adolescent↗
PubMed2004

Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.

Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the common gut bacterium Escherichia coli. We show here that keratinocytes secrete, as the main E. coli-killing compound, the S100 protein psoriasin in vitro and in vivo in a site-dependent way. In vivo treatment of human skin with antibodies to psoriasin inhibited its E. coli-killing properties. Psoriasin was induced in keratinocytes in vitro and in vivo by E. coli, indicating that its focal expression in skin may derive from local microbial induction. Zn(2+)-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn(2+) sequestration could be a possible antimicrobial mechanism. Thus, psoriasin may be key to the resistance of skin against E. coli.

Anti-Bacterial Agents↗
PubMed2003

Association of human papillomavirus infections with cutaneous tumors in immunosuppressed patients.

Besides immunosuppression and UV radiation, human papillomavirus (HPV) infection was also suggested to be involved in the development of non-melanoma skin cancer, the most common malignancy after transplantation. In this study we used a comprehensive PCR assay to analyze the prevalence of individual HPV types in different skin lesions from transplant and non-transplant patients. HPV DNA was detected more frequently in squamous cell carcinomas (SCCs) of transplant recipients (75%) than the same lesion was in non-immunosuppressed patients (47%). Similar HPV prevalences were found in cutaneous warts (91% vs 94%), pre-malignant skin tumors (38% vs 36%), and normal skin specimens (17% vs 16%) of both patient populations. Overall, more than 40 different HPV types were identified. HPV types 5 and 8 were found more frequently in SCCs (26%) than in pre-cancerous (5%) or benign lesions (1%). All HPV 5- and HPV 8-positive SCCs were from immunosuppressed patients, indicating that infection with HPV 5 and HPV 8 may present an increased risk of SCC development in these patients.

Base Sequence↗
PubMed2003

An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis.

BACKGROUND: Alefacept, human lymphocyte function-associated antigen 3/immunoglobulin 1 fusion protein, binds to CD2 molecules on the surface of activated T cells, selectively targeting memory-effector (CD45RO+) T cells, which comprise more than 75% of T cells in psoriatic plaques. OBJECTIVE: To examine the efficacy and tolerability of intramuscular alefacept. DESIGN: International, randomized, double-blind, placebo-controlled, parallel-group trial. PATIENTS: A total of 507 patients with chronic plaque psoriasis. INTERVENTION: Placebo, 10 mg of alefacept, or 15 mg of alefacept administered once weekly for 12 weeks followed by 12 weeks of observation. MAIN OUTCOME MEASURE: Psoriasis Area Severity Index (PASI). RESULTS: Alefacept treatment was associated with dose-related significant improvements in PASI from baseline. Throughout the study, a greater percentage of patients in the 15-mg group than in the placebo group achieved a significant reduction in PASI. Of patients in the 15-mg group who achieved at least 75% PASI reduction 2 weeks after the last dose, 71% maintained at least 50% improvement in PASI throughout the 12-week follow-up. There were no opportunistic infections and no cases of disease rebound. CONCLUSION: Intramuscular administration of alefacept was a well-tolerated and effective therapy for chronic plaque psoriasis and thus represents a convenient alternative to intravenous dosing.

Adolescent↗
PubMed2003

Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study.

This prospective long-term cohort study investigated the incidence of malignancies in severe psoriasis patients treated with cyclosporine. A total of 1252 patients were followed prospectively for up to 5 y. Malignancies were recorded prospectively. Incidence rates for malignancies were compared with the general population using standardized incidence ratios. The effect of duration of exposure to cyclosporine and to previously administered anti-psoriatic treatments on the incidence of malignancies was investigated using Poisson regression models. The mean age of patients was 43 y and on average, patients received cyclosporine for 1.9 y. Malignancies were diagnosed in 47 patients (3.8%), 49% of them had skin malignancies. The standardized incidence ratio in the study cohort was 2.1 as compared with the general population. The higher incidence of malignancies was attributed to a 6-fold higher incidence of skin malignancies, most of which were squamous cell carcinoma. The incidence of nonskin malignancy overall was not significantly higher in this study than in the general population. Duration of exposure to cyclosporine, exposure to psoralen and ultraviolet A, exposure to methotrexate, and exposure to immunosuppressants showed a significant effect on the incidence of nonmelanoma skin malignancies. In conclusion, treatment of psoriasis with cyclosporine is associated with an increased risk of nonmelanoma skin cancer. Patients treated for more than 2 y with cyclosporine were shown to have a higher risk. In addition, exposure to psoralen and ultraviolet A and to other immunosuppressants was shown to contribute to the overall risk.

Adult↗
PubMed2002

Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease.

Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2-0.5 microg rhuIL-4 than at < or =0.1 microg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ Th1 cells; and the IFN-gamma/IL-4 ratio. In the circulation, 0.2-0.5 microg/kg rhuIL-4 increased the number of IL-4+CD4+ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.

Adolescent↗
PubMed2002

The role of the Duffy antigen-related chemokine receptor in psoriasis vulgaris.

Chemokines represent a family of potent biological mediators. Within the group of receptors mediating their effects, a promiscuous receptor has been found which is able to bind and inactivate diverse chemokines of both C-C and C-X-C families. It is co-localized with blood group antigens of the Duffy system on the same glycoprotein and expressed on red blood cells as well as post-capillary blood vessels. In the present study three aspects of Duffy pathophysiology were studied: firstly the amount of IL-8 and RANTES binding to red blood cells and its correlation to disease activity of psoriatic patients, secondly the distribution of Duffy phenotype among psoriatic patients and thirdly the expression of Duffy antigen in normal vs psoriatic skin. Red blood cells from psoriatic patients (n=50) were lysed by triton X (1%) and supernatants tested in IL-8- and RANTES sandwich-ELISA. Duffy phenotype of psoriatic patients (n=50) was assessed by typing red blood cells with specific antisera in indirect Coombs technique. For immunohistochemical detection in normal and psoriatic skin (n=10 respectively) a specific monoclonal antibody (Fy6) was used. Neither IL-8- nor RANTES-levels on red blood cells correlated to disease activity and distribution of Duffy phenotype in psoriatics was not significantly altered when compared to the normal population. Furthermore, Duffy antigen was expressed in a similar pattern in normal and psoriatic skin at all parts of vasculature, albeit much more abundantly in diseased skin. Altogether, chemokine binding to red blood cells seems of minor importance in psoriasis. However, Duffy antigen together with other binding mechanisms like proteoglycans may play a role at local level by binding locally produced chemokines. Thus biological effects of chemokines are both restricted and focussed to dermal tissue.

Adult↗
PubMed2002

Analysis of phenotypic variation in psoriasis as a function of age at onset and family history.

To evaluate the relationship between psoriasis disease severity, age at onset, and family history, we analyzed 537 US psoriatics, most of whom were from Michigan. Total body surface area involvement (%TBSA), presence or absence of joint complaints, and nail involvement were measured. Analysis of familial psoriatics revealed that %TBSA was 15.1% when onset was early, but only 8.7% when onset was late ( P=0.00003). The opposite trend was seen when psoriasis was sporadic: %TBSA was 14.3% when onset was early (</=40 years of age) compared to 28.0% when onset was late ( P=0.0034). However, the sporadic group was small and ascertainment of the sporadic group was biased for severe involvement. As determined by log-linear analysis, joint complaints and age at onset were not significantly associated after controlling for age at examination, nor were joint complaints and familial status. Psoriatic nail changes were conditionally independent of familial status, given age at onset; nail changes were more frequently encountered in early-onset patients. There was no significant difference in the frequency of carriage of the MHC psoriasis risk determinant in the familial vs sporadic groups. Early-onset psoriatics did carry this determinant significantly more frequently, as expected. These results demonstrate increased severity of skin and nail disease in early-onset psoriasis, when psoriasis is familial. The lack of clinical differences between "familial" and "sporadic" psoriasis may reflect a similar genetic basis for both conditions, at least when onset is early.

Adolescent↗
PubMed2002

A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses.

BACKGROUND: Actinic keratoses (AKs) are precancerous epidermal lesions found most frequently on areas of the skin exposed to the sun. Several case studies published recently have indicated that 5% imiquimod cream, currently licensed for the treatment of genital warts, may be an effective treatment for AK. OBJECTIVE: To assess the efficacy and safety of imiquimod for the treatment of AK. DESIGN: Patients in this randomized, double-blind, vehicle-controlled study applied 5% imiquimod cream or vehicle to AK lesions 3 times per week for a maximum of 12 weeks or until lesions had resolved. In the event of an adverse reaction, application of imiquimod was reduced to 1 or 2 times per week. Rest periods were also allowed if necessary. SETTING: A specialized outpatient dermatology clinic within a state-funded hospital in Germany. PATIENTS: The study population was aged 45 to 85 years. Of 52 patients screened, 36 men and women with AK confirmed by histological diagnosis were enrolled. Patients were excluded from the study if they did not have a histological diagnosis for AK, if they were older than 85 years, or if they did not comply with the protocol. All patients had responded to a notice asking for volunteers. MAIN OUTCOME MEASURES: The number and appearance of lesions were evaluated before, during, and after treatment. All adverse effects were recorded. RESULTS: Lesions treated with 5% imiquimod cream were clinically cleared in 21 (84%) of 25 patients and partially cleared in 2 (8%). Clearance was histologically confirmed 2 weeks after the last application of imiquimod in all patients clinically diagnosed as lesion free. Only 10% of patients treated with imiquimod were clinically diagnosed with recurrence 1 year after treatment. No reduction in the size or number of AK lesions was observed in vehicle-treated patients. Adverse effects reported by patients treated with imiquimod included erythema, edema, induration, vesicles, erosion, ulceration, excoriation, and scabbing. However, imiquimod was well tolerated since all patients completed the 12-week treatment. Only a few, mild adverse reactions to the vehicle cream were reported. CONCLUSION: Application of 5% imiquimod cream for 12 weeks is an effective and well-tolerated treatment for AK.

Adjuvants, Immunologic↗
PubMed2002

Cicatricial pemphigoid differs from bullous pemphigoid and pemphigoid gestationis regarding the fine specificity of autoantibodies to the BP180 NC16A domain.

Bullous pemphigoid (BP), pemphigoid (herpes) gestationis (PG), cicatricial pemphigoid (CP), and lichen planus pemphigoides (LPP) are autoimmune subepidermal bullous diseases that are characterized by circulating autoantibodies to the transmembrane hemidesmosomal protein BP180/type XVII collagen. Previous studies demonstrated that the majority of patients with BP, PG, and LPP show antibodies to an immunodominant, membrane-proximal non-collagenous domain (NC16A) on the extracellular portion of BP180. By the use of non-overlapping peptides of the NC16A domain, we previously demonstrated that autoantibodies from BP and PG patients mainly react with epitopes clustered within the N-terminus of this immunodominant site of BP180; antibodies from patients with LPP also recognized the C-terminal portion of NC16A. However, some of these results had been obtained indirectly by preadsorption studies. The aim of the present study was to analyze the fine specificity of IgG autoantibodies to NC16A in sera from patients with CP and to compare their reactivity with antibodies from BP, PG, and LPP patients using a series of new overlapping fragments covering the entire NC16A domain. We confirm that BP and PG sera mainly react with N-terminal epitopes of NC16A, whereas sera from patients with LPP also bind to C-terminal portions, of this domain. Interestingly, out of ten patients with CP, the sera of seven reacted with NC16A; within NC16A, these sera bound to both C-terminal fragments and an N-terminal epitope right next to the cell membrane. Our data demonstrate a heterogeneous binding pattern of autoantibodies to BP180 NC16A in patients with CP.

Antibody Specificity↗