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Biomedical subjects

C E M Griffiths

Publications and source records attributed to C E M Griffiths.

At least 19 recordsLinked to original sources
PubMed2003

A Crohn's disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis.

A C-insertion polymorphism in the NOD2 gene (3020insC) on chromosome 16 is a rare mutation associated with Crohn's disease. Crohn's disease and psoriasis are more commonly observed together than expected by chance. Furthermore a susceptibility locus for psoriasis has been identified on chromosome 16q which overlaps the recently identified susceptibility locus for Crohn's disease. Thus, NOD2 may potentially be important as a candidate susceptibility gene for psoriasis. We tested this hypothesis by genotyping psoriasis patients for the C-insertion polymorphism using the Taqman ABI 7700 sequencing system. No statistically significant differences were observed between psoriasis vulgaris (n = 216), palmo-plantar pustular psoriasis (PPP) (n = 100), guttate psoriasis (n = 118) and the control group (n = 283). In both patient and control groups, no mutant homozygotes were observed and approximately 4% were heterozygotes. This particular insertion mutation in the NOD2 gene does not appear to contribute to the genetic susceptibility of psoriasis vulgaris, PPP or guttate psoriasis. However, other mutations exist in the NOD2 gene, which may potentially have a role in psoriasis susceptibility.

Adolescent↗
PubMed2003

Circulating natural killer cells in psoriasis.

BACKGROUND: Psoriasis is an immunologically mediated, probably autoimmune, disease in which T-helper type 1 cytokines play an important role. Established autoimmune diseases, with similar mechanistic characteristics to psoriasis, include multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus and systemic lupus erythematosus. Natural killer (NK) and natural killer-T (NK-T) cells are considered key to the pathogenesis of these conditions, which are characterized by reduced numbers of NK cells in peripheral blood. NK and NK-T cells have been implicated in the pathogenesis of psoriasis and are present in plaques of psoriasis. OBJECTIVES: To investigate whether levels of NK and NK-T cells are reduced in the peripheral blood of patients with psoriasis. METHODS: Fourteen patients with untreated psoriasis, mean +/- SD age 46 +/- 13 years, and 13 healthy volunteers, mean +/- SD age 34 +/- 9 years, were venesected and peripheral blood mononuclear cells isolated, labelled with a panel of antibodies to T-cells and NK cells including CD3, CD56, CD57, CD16, CD94, CD158a, CD69 and cutaneous lymphocyte-associated antigen (CLA) and analysed using triple-colour flow cytometry. RESULTS: There were significantly fewer cells expressing the NK-cell markers CD16 (P < 0.001), CD56 (P < 0.003), CD94 (P < 0.001) and CD158a (P < 0.02) in patients with psoriasis compared with normal controls. However, circulating numbers of NK-T cells (CD3+ CD56+ CD57+), T-cells (CD3+), activated lymphocytes (CD69+) or CLA+ cells were not significantly different between patients with psoriasis and controls. CONCLUSIONS: Circulating NK cells are reduced in psoriasis. This finding is similar to those in established autoimmune diseases such as rheumatoid arthritis. This observation provides some evidence that psoriasis may be an autoimmune disease in which NK cells play a role.

Adult↗
PubMed2003

Development of the PSORIQoL, a psoriasis-specific measure of quality of life designed for use in clinical practice and trials.

BACKGROUND: Patients with psoriasis have significant impairment in their quality of life (QoL). Several patient-completed instruments are available to measure outcome in dermatological conditions but these primarily focus on severity of disease rather than on QoL. OBJECTIVES: To develop a new instrument specifically designed to measure QoL in psoriasis-the Psoriasis Index of Quality of Life (PSORIQoL). METHODS: The content of the instrument was derived from qualitative interviews with 62 psoriasis patients in the U.K., Italy and the Netherlands. Content analysis of the interview transcripts from the three countries identified potential items for the questionnaire. All further stages of the project were conducted in the U.K. only. Face and content validity were determined by means of a focus group held with seven psoriasis patients and face-to-face interviews with a further 21 patients. A new draft version of the PSORIQoL, together with the Dermatology Life Quality Index (DLQI) and the General Well-Being Index (GWBI), were completed by a new sample of psoriasis patients contacted by mail, in order to determine construct validity. A subsample of the respondents completed a similar package 2 weeks later, to assess reproducibility (reliability). RESULTS: The first version of the PSORIQoL consisted of 61 items covering the needs identified in the interviews as having been affected by psoriasis or its treatment. These included fear of negative reactions from others, self-consciousness and poor self-confidence, problems with socialization, physical contact and intimacy, limitations on personal freedom and impaired relaxation, sleep and emotional stability. Following the focus group and field-test interviews, a new draft measure consisting of 45 items was completed by 148 patients, 88 of whom completed and returned a similar package 2 weeks later. Application of Rasch analysis identified a final 25-item version of the PSORIQoL. This version had a test-retest reliability coefficient of 0.89, indicating good reproducibility. The levels of association with the DLQI and PGWB indicated that the PSORIQoL measures a related but distinct construct. CONCLUSIONS: The PSORIQoL appears to be a practical, reliable and valid instrument for measuring the impact of psoriasis on QoL. It remains necessary to establish the instrument's responsiveness to changes in QoL associated with treatment.

Adult↗
PubMed2003

Oral mucosal keratinocytes express RANTES and ICAM-1, but not interleukin-8, in oral lichen planus and oral lichenoid reactions induced by amalgam fillings.

Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa characterized by a band-like accumulation of lymphocytes in the connective tissue adjacent to the basement membrane as well as intraepithelially. Amalgam fillings can induce oral lichenoid reactions (OLR) that are similar to OLP. The adhesion molecule ICAM-1 and the chemokines interleukin-8 and RANTES all play central roles in leucocyte trafficking. The aim of this study was to investigate the possible role of these molecules in the migration of leucocytes into the oral mucosa in OLP and OLR. Standard immunoperoxidase techniques were used to visualize the expression of ICAM-1, RANTES and interleukin-8 in frozen biopsy sections. ICAM-1 was expressed by endothelial cells, but not by keratinocytes, in normal oral mucosa. ICAM-1 was expressed by keratinocytes in 11 of 12 biopsies of OLP and in six of seven biopsies of OLR. In all of these cases ICAM-1 was also expressed by endothelial cells and leucocytes. Although not present in normal oral mucosa, RANTES was expressed by keratinocytes in 21 of 24 biopsies of OLP and in seven of seven cases of OLR. Interleukin-8 was not detected in any of the samples. The expression of ICAM-1 and RANTES by epithelial keratinocytes in the oral mucosa in OLP and OLR could be a key inflammatory mechanism in these diseases.

Adult↗
PubMed2003

Keloidal scleroderma.

A 53-year-old woman with systemic sclerosis developed numerous cutaneous nodules, resembling keloids, on her anterior chest wall. The nodules failed to respond to therapy with topical steroid, calcipotriol, or extended photochemotherapy. This is a rare, disfiguring variant of scleroderma, unresponsive to treatment, and poorly understood.

Administration, Topical↗
PubMed2003

Papuloerythroderma of Ofuji associated with acute myeloid leukaemia.

Papuloerythroderma of Ofuji (PEO) is an uncommon skin condition most commonly described in Japan. The aetiology of PEO is unknown and treatment may be difficult. There are several reports of an association between PEO and malignancy, most particularly with T-and B-cell lymphomas. We describe PEO complicated by acute myeloid leukaemia occurring in a 62-year-old man. This association has not been reported previously.

Dermatitis, Exfoliative↗
PubMed2003

IL-1beta-induced Langerhans' cell migration and TNF-alpha production in human skin: regulation by lactoferrin.

In mice, the roles of cytokines in the initiation of epidermal Langerhans' cell (LC) migration are well documented; however, the mechanism of this response in humans is less well defined. The purpose of the present investigation was to examine the contribution of interleukin (IL)-1beta to human epidermal LC migration and to define further the mechanisms of this response. We demonstrate here that homologous recombinant IL-1beta administered intradermally to healthy human volunteers provides a stimulus for LC migration, with significant (P < 0.01) reductions in LC densities being observed at both 2 h and 4 h following treatment. At the later time-point of 4 h, injection of IL-1beta was also accompanied by activation of those LC remaining in the epidermis. Analysis of fluid aspirated from suction blisters formed at injection sites revealed significant (P < 0.01) tumour necrosis factor (TNF)-alpha production (2.99 +/- 1.18 pg TNF-alpha/mg protein; mean +/- s.d. of n = 10) in response to IL-1beta treatment compared with saline control injections (0.90 +/- 1.05 pg TNF-alpha/mg protein). Prior topical application of human recombinant lactoferrin (LF), an iron-binding protein found in exocrine secretions and skin, inhibited IL-1beta-mediated LC migration and also compromised the production of TNF-alpha protein as measured in suction blister fluids derived from each of the treatment sites. Taken together, these data demonstrate that IL-1beta is associated with both the stimulation of human epidermal LC migration and local TNF-alpha production. Topical treatment with LF compromises both these responses. These data suggest that topical LF may potentially represent a novel therapeutic in the treatment of skin inflammation where TNF-alpha is an important mediator.

Adult↗
PubMed2003

The immunological basis of psoriasis.

Evidence that psoriasis is an immune-mediated disorder comes from laboratory studies, clinical observation, and use of targeted therapies. Immunohistochemical studies have shown that the majority of T cells in psoriatic plaques are CD45RO+ memory-effector T cells that migrate into skin in recognition of an as yet undetermined antigen. There is also a predominance of Th1 cytokines, namely interferon gamma, in psoriatic plaques, in contrast to the predominance of Th2 cytokines found in atopic dermatitis. The efficacy of therapeutic agents that target T cells, such as anti-CD4+ monoclonal antibodies, cyclosporin, and interleukin-2 fusion toxin, has provided further substantial evidence that psoriasis is a T-cell-mediated disease. New T-cell targeted approaches and cytokine modulation are advancing basic science in providing an understanding of the evidence for the importance of the immune process in the biology of psoriasis.

Antibodies, Monoclonal↗
PubMed2003

Calcium homeostasis remains unaffected after 12 weeks' therapy with calcitriol 3 microg/g ointment; no correlation with extent of psoriasis.

OBJECTIVE: To assess the systemic safety of calcitriol 3 microg/g ointment (Silkis) ointment) in relation to body surface area (BSA) affected by chronic plaque psoriasis. METHODS: In this open-label, multicentre study, patients were divided into three parallel groups: 5% to <15% (n=23), 15% to <25% (n=18), 25% to 35% (n=18) based on BSA involvement. Ointment was applied topically twice daily for 12 weeks; patients were followed up for a further 8 weeks. RESULTS: There was no alteration of calcium homeostasis: the mean values of albumin-adjusted serum total calcium, as well as 24-hour urinary calcium and serum calcitriol levels, remained within normal ranges throughout treatment. No changes in calcium or phosphate homeostasis related to the area of psoriasis being treated with calcitriol ointment were detected. CONCLUSIONS: Reductions in the global severity score and BSA involvement, as well as results of the assessment of improvement, attested to the clinical efficacy of calcitriol 3 microg/g ointment in psoriasis. The study confirms the systemic safety of calcitriol 3 microg/g in psoriatic patients with 5-35% BSA involvement.

Administration, Cutaneous↗
PubMed2002

Natural killer and natural killer-T cells in psoriasis.

Psoriasis is characterized by a dermal and epidermal infiltrate comprised predominantly of CD4(+) and CD8(+) T cells, respectively. These cells behave in an antigen-dependent manner, which suggests that psoriasis may be a T-cell-mediated autoimmune disease. Psoriasis shares certain immunological features with recognized autoimmune conditions such as type I diabetes mellitus and multiple sclerosis, in both of which a pathogenic role is postulated for natural killer (NK) cells and natural killer-like T (NK-T) cells. However, there are few studies assessing the role of NK and NK-T cells in psoriasis. We sought to determine whether NK and NK-T cells are present in psoriasis. Skin biopsies were taken from the active edge of a psoriasis plaque and from uninvolved skin at least 5 cm away from involved skin of ten patients with chronic plaque psoriasis. Skin from four normal subjects was used as controls. Using an immunoperoxidase technique, cryostat sections were stained using antibodies to T-cell markers CD2, CD3, CD4 and CD8; cutaneous leucocyte associated antigen; NK cell markers CD16, CD56, CD57, CD94 and CD158a; and the NK-T cell marker CD161. There were significantly more cells expressing T cell markers, NK cell markers CD16, CD57, CD94 and CD158a and NK-T cell marker CD161 in involved skin than in uninvolved or normal skin ( P<0.01). There was no difference in the number of cells expressing CD56. Cells expressing NK markers were found most commonly in the papillary dermis immediately subjacent to the dermoepidermal junction. Cells expressing CD57 were found in significantly higher numbers in the epidermis and reticular dermis of involved skin. This study demonstrates that cells expressing NK markers and NK-T cell markers are present in plaques of psoriasis. The exact roles of NK and NK-T cells in psoriasis are unclear, although they may modulate autoimmune inflammation and act as a source of Th(1) cytokines important in the psoriatic process.

Adult↗
PubMed2002

Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing.

BACKGROUND: Langerhans cells (LCs) play essential roles in the initiation and regulation of cutaneous immune responses mediated through their successful migration from the epidermis to draining lymph nodes while carrying antigen. Tumour necrosis factor (TNF)-alpha, a keratinocyte-derived cytokine, has recently been shown to play an important role in the mobilization of LCs from human epidermis. Although it is known that with age the immune system changes, the influence of increasing age on the function of human LCs has not been defined clearly. OBJECTIVES: To examine the influence of age on the ability of TNF-alpha to induce LC migration. METHODS: Ten elderly (six men, four women; mean age 76 years, range 72-79) and 10 young (six men, four women; mean age 23 years, range 18-35) volunteers received intradermal injections of 200 U of human recombinant TNF-alpha diluted in sterile saline, and control injections of sterile saline alone, at each of two paired sites identified on photoprotected buttock skin. Two hours later, paired injection sites were excised by punch biopsy. One set of paired biopsies was processed for assessment of the frequency and morphology of epidermal LCs, following preparation of epidermal sheets and immunofluorescence staining for the LC marker CD1a. The remaining paired biopsies were processed in formalin and the inflammatory response to TNF-alpha was assessed by standard histological examination. RESULTS: Mean +/- SEM baseline values for LC frequency within epidermal sheets were significantly different between young (1156.3 +/- 38.5 cells mm(-2)) and elderly subjects (835.7 +/- 48.2 cells mm(-2); P < 0.01). Intradermal injections of 200 U of TNF-alpha caused a significant reduction in the frequency of LCs in both elderly and young subjects (P < 0.01). However, the extent of TNF-alpha-induced LC migration was substantially different between the two groups, with a mean 9% reduction in LC frequency in elderly volunteers compared with a mean 23% decrease in young subjects. Exposure to TNF-alpha was associated with a perivascular polymorphonuclear infiltrate at 2 h in all young subjects; in contrast, only 50% of the elderly individuals showed evidence of such a response. CONCLUSIONS: There are significant differences between young and old skin with respect to both resting LC numbers and their response to TNF-alpha. These age-related changes in LC frequency and function may contribute to the altered cutaneous immune function observed in the elderly.

Adolescent↗
PubMed2002

Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis.

BACKGROUND: As psoriasis patients often require continuous treatment optimal therapy has to provide efficacy and a good safety profile over the long term. OBJECTIVES: The aim of this multicentre study was to assess the efficacy, safety and tolerability of tacalcitol (4 microg g(-1)) ointment (Curatoderm, Hermal, Reinbek, Germany) applied once daily over a treatment period of 18 months. PATIENTS AND METHODS: Efficacy parameters were Psoriasis Area Severity Index (PASI), based on summed scores of erythema, infiltration and scaling and total body surface involvement (TBI). Safety assessment included serum levels of calcium, parathyroid hormone, calcitonin, 1,25-dihydroxy vitamin D3 (calcitriol); urinary calcium, creatinine, calcium/creatinine ratio in spot and 24-h urine and urinary alpha(1)-microglobulin. A group of 304 patients with chronic plaque psoriasis, covering between 7% and 20% of the body surface area was included for the initial treatment phase of 3 months. Of the 257 patients who completed the initial 3 months, 197 patients continued in a second treatment phase of 15 months. RESULTS: Tacalcitol treatment proved to be effective in reducing the severity of psoriasis and maintained therapeutic response over the study period. The median PASI fell from 9.5 to 4 .6 at month 3 and to 3.25 at month 18 (P < 0.0001). The median improvement in TBI was 30% at month 3 and 50% at month 18. In no patient was there any relevant disturbance of calcium homeostasis. There were no significant changes in mean values of serum calcium, parathyroid hormone and calcitriol. Additionally no significant changes in 24-h urinary excretion evaluation were observed. There was no correlation between levels of serum calcium or urinary calcium and amount of tacalcitol ointment used, even in the patients requiring the largest amounts of ointment (up to 13 g day(-1) and up to 20% of body area affected). Treatment was generally well tolerated and there were no serious or unexpected adverse events reported. However, discontinuation of treatment as a result of skin irritation was seen in 5.9% of patients. The greatest frequency of cutaneous side-effects occurred during initial treatment and the incidence decreased markedly as the treatment was well-tolerated with continued use. CONCLUSIONS: Tacalcitol ointment once daily was demonstrated to be efficacious, safe and well tolerated in the long-term control of plaque psoriasis in patients with up to 20% body surface involvement.

Adolescent↗
PubMed2002

A cognitive-behavioural symptom management programme as an adjunct in psoriasis therapy.

BACKGROUND: Patients with psoriasis may experience significant psychological and social disabilities. Stress or distress are proposed aggravators of the disease process in psoriasis. Preliminary studies to date have suggested that adjunctive psychological therapies may be effective in the clinical management of psoriasis. OBJECTIVES: To examine whether a 6-week multidisciplinary management approach, the Psoriasis Symptom Management Programme (PSMP) for patients with psoriasis improves clinical severity of psoriasis and its associated psychological distress and disability. METHODS: In a case-control study, patients with psoriasis attending an out-patient psoriasis specialty clinic chose to receive standard psoriasis treatment alone (n = 53) or to enter the PSMP as an adjunct to standard therapy (n = 40). They were assessed at baseline, at the end of the 6-week PSMP and after 6 months follow-up. RESULTS: As compared with standard treatment alone, analysis of covariance indicated that participation in the PSMP resulted in a greater reduction in clinical severity of psoriasis (P = 0.001), anxiety (P = 0.001), depression (P = 0.001), psoriasis-related stress (P = 0.001) and disability (P = 0.04) at 6 weeks and 6 months follow-up. CONCLUSIONS: The management of the physical aspects of psoriasis and its psychological effects are significantly improved for patients who opt for a 6-week integrated multidisciplinary approach. Furthermore, the techniques learnt by participation in the PSMP facilitate continued control of psoriasis for at least 6 months.

Administration, Topical↗
PubMed2002

Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial.

BACKGROUND: Skin-homing, memory T lymphocytes play an important role in the pathogenesis of psoriasis by interacting with the vascular addressin, E-selectin and trafficking into lesional skin. Thus an attractive option for targeted therapy of the disease would be blockade of skin-homing T cells with an antibody directed at E-selectin. OBJECTIVE: We performed a multicentre, randomized, placebo-controlled trial to investigate the clinical efficacy and side-effect profile of a humanized monoclonal antibody to E-selectin, CDP850, in the treatment of moderate to severe chronic plaque psoriasis. METHODS: Patients with moderate/severe chronic plaque psoriasis were selected for study. Nine male subjects (mean age 37 years, range 25-47) were given 20 mg kg-1 CDP850 intravenously as a single dose and four subjects (three males, one female; mean age 40 years, range 23-50) received placebo infusion. Clinical response to treatment was assessed using the psoriasis area and severity index (PASI). Skin biopsies were taken for immunohistochemical analysis at the baseline, pretreatment, visit and also at day 2 and weeks 1 and 4 postinfusion. RESULTS: The treatment was well-tolerated with a minimal side-effect profile. Plasma E-selectin levels were significantly decreased in those subjects who received CDP850 compared with those who had placebo for the entire study period. At the end of study (8 weeks postinfusion), there was no significant reduction in PASI from baseline for either the CDP850 or placebo-treated groups. Immunohistochemical analysis of biopsies taken from lesional psoriatic skin showed that 2 days after dosing with CDP850, staining for E-selectin was decreased, although not absent, on dermal vascular endothelial cells when compared with baseline (P < 0.01). This decrease in E-selectin expression was maintained 4 weeks after infusion (P < 0.05). It was not, however, accompanied by a significant reduction in numbers of neutrophils or lymphocytes in the dermis. There was a statistically significant increase in CD1a-positive epidermal Langerhans cells compared with pre-dose levels at week 1 (P < 0.05). CONCLUSIONS: This clinicopathological study shows that anti-E-selectin (CDP850), although a well-tolerated, logical and safe therapy, does not appear to possess a therapeutic role in the treatment of chronic plaque psoriasis.

Adult↗
PubMed2002

Novel immune-based therapies for psoriasis.

The primacy of the immune system in the pathogenesis of psoriasis is a well-established concept to the extent that psoriasis has been classified as a T-cell-mediated, autoimmune disease. An explosion of knowledge concerning immunological events in psoriasis and the clinical efficacy of immunologically directed therapies, such as cyclosporin, support this concept. Armed with this understanding and modern biotechnology, novel interventions have been developed to treat psoriasis. The aim of these therapies is to provide selective, immunologically directed intervention with the hope that such specificity will result in fewer side-effects than traditional therapies. Of interest and importance, these pharmaceutical interventions also act as a form of investigational tool in psoriasis. Their relative efficacy in the psoriatic process provides useful insights into the hierarchial importance of immune events in the disease process and recent evidence suggests that innate rather than acquired immunity has a key role. This article reviews recent developments in immune-based therapies for psoriasis.

Cytokines↗
PubMed2002

Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17-butyrate cream for the treatment of atopic dermatitis.

BACKGROUND: Therapeutic options to treat atopic dermatitis are limited. Leukocytes from atopic patients have an abnormally high activity of cyclic adenosine monophosphate (AMP)-phosphodiesterase (PDE), which can be normalized in vitro by PDE inhibitors. Cipamfylline is a new potent and selective inhibitor of PDE-4. OBJECTIVES: To compare the efficacy and safety of up to 14 days' topical treatment with cipamfylline (0.15%) cream with vehicle and with hydrocortisone 17-butyrate (0.1%) cream. PATIENTS AND METHODS: International, multicentre, prospective, randomized double-blind, left-right studies of cipamfylline vs. vehicle and cipamfylline vs. hydrocortisone 17-butyrate in adult patients with stable symmetrical atopic dermatitis on the arms. RESULTS: Both cipamfylline and hydrocortisone 17-butyrate reduced the Total Severity Score significantly (P < 0.001). The reduction with cipamfylline was significantly greater than that with vehicle (difference vehicle-cipamfylline 1.67 95% confidence interval (CI) 1.06, 2.28; P < 0.001) and was significantly less than with hydrocortisone 17-butyrate (difference hydrocortisone-cipamfylline -2.10 95% CI -2.93, -1.27; P < 0.001). Investigator and patient assessments of the overall treatment response showed a similar picture. CONCLUSIONS: Cipamfylline cream is significantly more effective than vehicle, but significantly less effective than hydrocortisone 17-butyrate cream in the treatment of atopic dermatitis.

Administration, Topical↗
PubMed2002

Recent advances in cutaneous angiogenesis.

An understanding of the molecular basis of angiogenesis is key to the appreciation of many of the advances made in the field of neovascularization over the past two decades. The sequence of events involved in angiogenesis includes: (i) increased vascular permeability and leakage; (ii) degradation of basement membrane; (iii) endothelial cell proliferation and migration through the surrounding extracellular matrix; and (iv) maturation and stabilization of the newly formed vessel bed. This review provides an update on the molecular basis of such pathways in the skin, with particular emphasis on the endothelial cell-specific vascular endothelial growth factor and angiopoietins as modulators of angiogenesis that can be targeted in therapy of cutaneous disease.

Angiogenesis Inducing Agents↗