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Biomedical subjects

Christopher E M Griffiths

Publications and source records attributed to Christopher E M Griffiths.

At least 37 records · Page 2Linked to original sources
PubMed2004

Retinoic acid receptor alpha expression and cutaneous ageing.

Intrinsic ageing of human skin is a subtle and gradual process that demonstrates few clinical or histological features until old age (>70 years). Initial work indicates that aged skin is "retinoid sensitive" but there is little data on the role of retinoic acid receptors (RARs) or retinoid X receptors (RXRs) in skin ageing. As nuclear retinoid receptors have been implicated in ageing in rodents, we studied the distribution of these receptors in intrinsically aged as compared to young, photoprotected human skin. We found that intrinsic ageing of skin in vivo is accompanied by significant increases of RAR alpha mRNA and protein whereas other isoforms show no alteration with age. In vitro transfection of COS-1 cells with the RAR alpha gene induces expression of matrix metalloproteinase-1 (MMP-1), an enzyme known to play an active role in remodelling of the dermis in intrinsically aged and photoaged skin. Furthermore, addition of all-trans retinoic acid (RA) to cultures of RAR alpha-transfected COS-1 cells diminishes RAR alpha and returns levels of MMP-1 to those approaching baseline. These results demonstrate that intrinsic ageing of human skin is accompanied by significant elevation in the content of RAR alpha and that over-expression of RAR alpha influences expression of MMP-1, an important mediator of skin ageing.

Adult↗
PubMed2004

The impact of psychological and clinical factors on quality of life in individuals with atopic dermatitis.

OBJECTIVE: The aim of the study was to assess the influence of general and dermatitis-specific psychological and clinical factors on quality of life in adults with atopic dermatitis (AD). METHOD: A total of 125 adults recruited through the National Eczema Society of U.K. (NES) completed a number of psychological and dermatological questionnaires, including the Dermatology Life Quality Index (DLQI), the Stigmatisation and Eczema Questionnaire (SEQ), the Hospital Anxiety and Depression Scale (HADS), the Fear of Negative Evaluation Scale (FNE) and the Rosenberg Self-Esteem Scale (RSE). RESULTS: Pearson's correlational analyses suggested that perceptions of stigma were significantly associated with psychological factors as well as quality of life (Ps<.01). An association was also found between perceived stigma and disease severity (-.28, P<.01). Almost 46% of participants were identified as having probable mood disorder. Regression analysis indicated that perceptions of stigma and depression accounted for 44.5% of the variance in quality of life in this sample [F(3,121)=34.18, P<.001], when disease severity was controlled for. CONCLUSION: Psychological factors and disease severity were strong predictors of quality of life in adults with AD. AD-related perceptions of stigma were of particular importance in predicting AD-related quality of life over and above more general psychological factors, such as depression. These findings have important implications for the psychological and clinical management of AD.

Adult↗
PubMed2004

Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset.

Vascular endothelial growth factor (VEGF)--a stimulus of angiogenesis--is produced by epidermal keratinocytes, and elevated levels have been found in plaques of psoriasis. Polymorphisms in the VEGF gene regulate production of VEGF. We postulated that patients with psoriasis may have altered systemic expression of VEGF consequent upon programming at the genomic level. We investigated the genetic basis of VEGF expression in patients with type 1 (onset before age 40 y) chronic plaque psoriasis compared to healthy controls and also measured plasma levels of VEGF and its receptors flt-1 and KDR. Patients with severe disease, and those with onset of psoriasis between the ages of 20 and 40 y showed significantly increased frequency of the +405 CC genotype (p=0.04 and p=0.02) and the C allele (p=0.03 and p=0.02), respectively, compared to healthy controls. Plasma levels of VEGF and flt-1 were significantly detectable in patients with psoriasis compared with controls (p<0.001); by contrast, mean plasma levels of KDR in psoriatic patients were comparable with controls. These results suggest that alterations in the biology of VEGF may be involved in the pathogenesis of psoriasis. VEGF, flt-1, and KDR could provide attractive targets for future psoriasis therapy.

Adolescent↗
PubMed2004

Divergent beliefs about psoriasis are associated with increased psychological distress.

The psychological adjustment of patients with psoriasis has been studied extensively. By comparison, no research has focused on their partners. We examined illness representations of psoriasis held by patients and their partners, and investigated whether divergent beliefs were associated with psychological distress. Fifty-eight patients with chronic plaque psoriasis and their partners completed a range of psychological assessments including beliefs about the condition, anxiety, depression, and worry. Patients also completed a self-assessment of psoriasis severity. Patients with psoriasis had significantly higher levels of anxiety, depression, and worry than their partners (t's > 2.53, p's < .05). Multiple regression analysis indicated that divergence in patients' and partners' beliefs about emotional impact of psoriasis and chronicity of timeline accounted for a statistically significant (21.3%) proportion of the variance in depression for partners. Differences in views on the consequences of having psoriasis and the cyclical nature of the condition were also significantly associated with increased levels of worry in partners. Dissimilarity in particular aspects of illness representations are associated with increased psychological distress in particular for the partners of patients with psoriasis. The results illustrate the importance of concordance between patients' and partners' models of illness in relation to adjustment, and highlight the need to consider and collaborate with both patients and their partners in managing this challenging condition.

Adaptation, Psychological↗
PubMed2004

Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis.

Macrophage migration inhibitory factor (MIF), an important pro-inflammatory cytokine, is over-expressed in plaques of psoriasis and increased levels are found in the sera of patients with psoriasis. Promoter polymorphisms of the MIF gene are associated with increased production of MIF and have been found to confer increased risk of susceptibility to chronic inflammatory diseases. We investigated whether there is an association between promoter polymorphisms of the MIF gene and chronic plaque psoriasis. Two hundred and twenty-eight UK caucasian patients with chronic plaque psoriasis, and a control panel of 401 UK caucasian normal volunteers were studied. MIF promoter polymorphisms were genotyped by allelic discrimination, or by a fluorescently labeled primer method, and capillary gel electrophoresis. Carriage of either the MIF-173*C polymorphism or the MIF CATT(7) polymorphism was positively correlated with psoriasis (odds ratios (OR) 1.52 95% confidence intervals (CI) 1.05-2.19 (p=0.024) and OR 1.67 95% CI 1.1-2.5 (p=0.013), respectively. The OR for presence of the CATT(7)-MIF-173(*)C haplotype versus all other haplotypes combined was 1.69 95% CI 1.2-2.5 (p=0.008). The results provide evidence for polymorphisms in the MIF gene, and in particular the CATT(7)-MIF-173(*)C haplotype, being of importance in susceptibility to psoriasis.

Adult↗
PubMed2004

Measurement of cytokine expression and Langerhans cell migration in human skin following suction blister formation.

Contact allergen-induced migration of epidermal Langerhans cells (LCs) to draining lymph nodes is dependent upon receipt by LCs of at least two cytokine signals provided by tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta. It has been reported previously that intradermal injection of healthy human volunteers with homologous TNF-alpha or IL-1beta each induces a significant reduction in LC frequency, as measured in epidermal sheets prepared from 6-mm punch biopsies. In the current experiments, we have compared the frequency of LCs in punch biopsies with those obtained concurrently in epidermal sheets from the roofs of suction blisters isolated from the sun-protected buttock skin of healthy adult volunteers. There was a significant, approximately 30%, reduction in CD1a(+) LC numbers in suction blister roofs compared with punch biopsies. Injection of homologous recombinant IL-1beta, a stimulus that provokes measurable epidermal LC mobilization in punch biopsy sites, failed to provoke further LC migration in suction blister sites. These data suggest that the mechanical trauma to the skin caused by the creation of suction blisters provokes the degree of cutaneous inflammation necessary for LC mobilization. The responsive cells (only a proportion of resident LCs, approximately 30%) have already migrated, thus addition of an exogenous cytokine signal (IL-1beta) is without further effect. It is not possible therefore to measure the regulation of LC mobilization by exogenous cytokines in suction blister roofs. However, this technique provides an opportunity to profile induced changes in the cutaneous cytokine environment, with cytokine expression measured by a multiple cytokine array system. Using this technique, intradermal injection of IL-1beta was found to cause a marked upregulation of proinflammatory cytokines including TNF-alpha, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1) and the anti-inflammatory cytokine IL-10 in fluid from suction blisters raised at the site of injection. In conclusion, the suction blister technique appears to be a powerful tool for measurement of induced changes in cutaneous cytokines.

Adult↗
PubMed2004

Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype.

Differences in glucocorticoid (GC) sensitivity may underlie both common diseases (e.g. hypertension) and variability in response to treatment with GCs (e.g. asthma). We tested the potential involvement of the GC receptor (GR) gene in mediating GC sensitivity using haplotype analysis and a low-dose dexamethasone suppression test. Linkage disequilibrium across the GR gene was determined in 216 U.K. Caucasians, and 116 had a 0.25-mg overnight dexamethasone suppression test. Very strong linkage disequilibrium was observed across the GR gene with only four haplotypes accounting for 95% of those observed. Haplotype pattern mining and linear regression analyses independently identified a three-marker haplotype, across intron B, to be significantly associated with low postdexamethasone cortisol (P = 0.03). Carriage of this haplotype occurred in 41% of the individuals with low postdexamethasone cortisol vs. 23% in the combined other quartiles (odds ratio 2.4, 95% confidence interval 0.9-6.3, P = 0.05). This is the first comprehensive, haplotype based analysis of the GR gene. A three-point haplotype, within intron B, is associated with enhanced sensitivity to GCs. This haplotype may help predetermine variation in clinical response to GC therapy and also assist the understanding of diseases related to GC production.

Adult↗
PubMed2004

Targeting cognitive-behaviour therapy to patients' implicit model of psoriasis: results from a patient preference controlled trial.

OBJECTIVES: The purpose of this study was to investigate the effects of a cognitive-behavioral psoriasis symptom management programme (PSMP) on patient-held perceptions about their condition and patients' use of self-reported coping strategies, and to examine the influence of alexithymia scores at induction on response to treatment. DESIGN: Age- and sex-matched case-controlled prospective study. METHODS: A total of 40 patients with psoriasis were treated in the PSMP, and an age- and sex-matched cohort received standard pharmacological care only. The Illness Perception Questionnaire was used to assess patients' beliefs about illness identity, time-line, consequences, cure/control and perceptions of the cause of their psoriasis. Participants also completed the COPE questionnaire and the Toronto Alexithymia Scale (TAS-20). RESULTS: Results suggested that at 6-month follow-up, patients who chose the PSMP showed significant reductions in illness identity (the frequency and severity of symptoms that patients associate with their condition), the strength of belief in severity of consequences of their illness, and their attributions for emotional causes of their psoriasis. Perceptions about the anticipated course of the disease (time-line), its cure or controllability, ideas about physical agents of causation, and coping strategies did not differ between PSMP patients or controls at 6-week or 6-month follow-up. Alexithymia had no effect on response to treatment. Regression analyses demonstrated the importance of both participation in the PSMP and demographic/clinical history variables in accounting for significant variance in illness-perception-change scores. CONCLUSION: The findings are generally supportive of multivariate models of intervention, but the lack of a demonstrated effect of the intervention on coping may have implications for both the assessment of coping in psoriasis and the nature of psychological interventions proposed for its management.

Adaptation, Psychological↗
PubMed2004

Therapeutic potential of macrolide immunosuppressants in dermatology.

Dermatologists are frequently presented with inflammatory dermatoses that are responsive to treatment with immunomodulating drugs. Corticosteroids, particularly when applied topically, have been the mainstay of treatment in the past. Their undoubted efficacy, however, has been undermined by problems with repeated use including tachyphylaxis and side effects such as skin atrophy and hypertension. Macrolide immunosuppressive drugs, originally used for prophylaxis of organ transplant rejection, have been shown to be effective in the treatment of inflammatory dermatoses. The original drugs used in dermatology in this class have their own limitations including poor absorption when used topically and their distinct side-effect profiles. A search for other immunosuppressive macrolide antibiotics has led to the development of new agents, which have enhanced profiles for the treatment of skin disease. This review discusses the main dermatoses that may be targeted by this class of drugs and summarises the topical and systemic macrolides either currently in use, in clinical trials or preclinical development.

Clinical Trials as Topic↗
PubMed2004

T-cell-targeted biologicals for psoriasis.

Psoriasis is now accepted as a T-cell-mediated disease and that targeting of T cell function and/or trafficking is a logical approach to therapy. As a consequence of recombinant DNA technologies biologic therapies are synthesisable in sufficient quantities for clinical use. The original proof of concept for T-cell-targeted therapies in psoriasis came with the demonstration that anti-CD4 monoclonal antibodies were effective. Progress is such that two T-cell-directed biologicals - alefacept and efalizumab - have recently been approved in the U.S.A. for the treatment of psoriasis. In addition to providing new therapies the T-cell-targeted biologicals with their selective approach can be used as sophisticated tools to dissect out and help our understanding of key pathomechanisms in psoriasis; the non - efficacy of anti - E-selectin is a case in point. It is likely that the most appropriate place for T-cell-directed biologicals in the management of chronic plaque psoriasis will be for maintenance, rather than induction, of remission. This is a reflection of mode of action and relative safety for long-term administration.

Alefacept↗
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

Psychological distress impairs clearance of psoriasis in patients treated with photochemotherapy.

OBJECTIVE: To assess whether psychological distress affects treatment outcome in psoriasis. DESIGN: Cohort study of patients with psoriasis receiving psoralen-UV-A (PUVA) photochemotherapy. SETTING: Two university hospital dermatology departments. PATIENTS: One hundred twelve patients with chronic plaque psoriasis. MAIN OUTCOME MEASURES: We assessed clinical severity of psoriasis, psychological distress, and other potential confounders of treatment outcome such as skin phototype, family history of psoriasis, and alcohol intake before starting PUVA therapy. Clinical severity of disease and response to therapy were assessed at every fourth appointment. RESULTS: Pathological or high-level worry was the only significant (P =.01) predictor of time taken for PUVA to clear psoriasis. Event curves of time to clearance significantly differed between high- and low-level worry groups (log rank test, 6.64; df = 1; P =.01). Patients in the high-level worry group cleared with PUVA treatment at a rate 1.8 times slower than that of the low-level worry group (ExpB = 1.81; 95% confidence interval, 1.13-2.90). Fiftieth percentile time to clearance of psoriasis in the high- and low-level worry groups showed a median difference of 19 days. CONCLUSIONS: Psychological distress, in the form of excessive worrying, has a significant and detrimental affect on treatment outcome in patients with psoriasis. Patients with psoriasis who are classified as high-level worriers may benefit from adjunctive psychological intervention before and during treatment. These findings provide further evidence of the existence of a brain-skin axis.

Adult↗
PubMed2003

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis.

The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other. We have genotyped the three psoriasis vulgaris susceptibility alleles of the PSORS1 locus in two clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis) to study whether PSORS1 is also involved in the pathogenesis of these variants. We also asked whether these two clinical subgroups could help us to distinguish the causative gene within the high-risk PSORS1 haplotype. The association of guttate psoriasis with the three PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the three candidate genes at this locus. Finally, no correlation with the age of onset for disease was observed. Our results show conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.

Diagnosis, Differential↗
PubMed2003

Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial.

BACKGROUND: Adapalene is a synthetic retinoid with an established clinical efficacy against acne and good local tolerability. Its effectiveness in the treatment of photodamaged skin has not been studied. OBJECTIVE: We sought to determine the safety and efficacy of adapalene gel in the treatment of actinic keratoses and solar lentigines. METHODS: In a prospective, 2-center, randomized, controlled, investigator-masked, parallel-group study, 90 patients with actinic keratoses and solar lentigines were treated daily with either adapalene gel (0.1% or 0.3%) or its vehicle gel for 4 weeks, followed by twice-daily applications, if tolerated, for up to 9 months. RESULTS: Of the 90 Caucasian patients (69 male, 21 female; mean age 63.1 years) who were enrolled into the study, 83 patients completed 9 months of treatment. With adapalene gel 0.1% and 0.3%, the mean number of actinic keratoses was reduced by 0.5 +/- 0.9 (mean +/- SE) and 2.5 +/- 0.9, respectively. Whereas, with the vehicle gel, there was an increase of 1.5 +/- 1.3 (P <.05). After 1 month of treatment, the patients who received adapalene had significant lightening of solar lentigines as compared with the patients who were treated with vehicle gel (P <.05). After 9 months, 57% and 59% of the patients had lighter lesions in the adapalene 0.1% and 0.3% groups, respectively, in comparison with only 36% in the vehicle group (P <.05). Histologic evaluations revealed improved cellular atypia and reduced epidermal melanin in adapalene-, as compared with vehicle-treated group. The differences, however, were not statistically significant. A retrospective evaluation of paired clinical photographs (before and after 9-month treatment) by 2 dermatologists who were treatment-blinded revealed significant improvement in wrinkles and other clinical features of photoaged skin with adapalene as compared with its vehicle. CONCLUSION: Adapalene gel 0.1% and 0.3% were well tolerated and improved actinic keratoses, solar lentigines, and other features of photodamaged skin.

Adapalene↗