Psoriasis: Reynolds NJ

Smith CH, Anstey AV, Barker JN, Burden AD, Chalmers RJ, Chandler D, Finlay AY, Griffiths CE, Grifitths CE, Jackson K, McHugh NJ, McKenna KE, Reynolds NJ, Ormerod AD, Anonymous00078. · St John's Institute of Dermatology, GKT School of Medicine, St Thomas' Hospital, London SE1 7EH, UK. · Br J Dermatol. · Pubmed #16120132 No free full text.

This publication has no abstract.

Weatherhead S, Robson SC, Reynolds NJ. · Dermatological Sciences, Institute of Cellular Medicine, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH. · BMJ. · Pubmed #17556479 No free full text.

This publication has no abstract.

Reynolds NJ, Al-Daraji WI. · Department of Dermatology, Medical School, University of Newcastle upon Tyne, UK. · Clin Exp Dermatol. · Pubmed #12464150 No free full text.

Abstract: Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non-inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer-term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non-immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.

Hampton PJ, Ross OK, Reynolds NJ. · Dermatological Sciences, Institute of Cellular Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK. · Br J Dermatol. · Pubmed #17916213 No free full text.

Abstract: BACKGROUND: Psoriasis is a common inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation, increased angiogenesis and inflammation. There is evidence that some keratinocyte differentiation events are controlled by changes in cell-cell adhesion. beta-catenin is a 94-kDa protein which has a dual function as a component of intercellular adherens junctions and also as a transcription factor as part of the Wnt signalling pathway. beta-catenin is not required for keratinocyte proliferation but has been shown to regulate keratinocyte stem cells and hair follicle morphogenesis. OBJECTIVES: To investigate the distribution and function of beta-catenin in involved psoriatic epidermis and in epidermal keratinocytes. METHODS: Biopsies were obtained from patients with psoriasis and from normal controls. The distribution of beta-catenin was investigated using antibodies to both total and unphosphorylated active beta-catenin. Luciferase assays were used to measure transcriptional activation of transglutaminase 1 (TGase 1) and involucrin and to investigate the functional role of beta-catenin in interfollicular keratinocytes. RESULTS: Increased nuclear beta-catenin was seen in lesional suprabasal psoriatic epidermis compared with uninvolved or normal skin. Increased active unphosphorylated beta-catenin was also detected within the differentiating compartment of involved psoriatic epidermis. Expression of TGase 1 overlapped with beta-catenin in suprabasal lesional psoriasis. The TGase 1 promoter was positively regulated by activated beta-catenin and by the glycogen synthase kinase binding protein, suggesting that beta-catenin and glycogen synthase kinase 3beta may regulate TGase 1 expression. CONCLUSIONS: This is the first report to convincingly demonstrate increased beta-catenin in involved psoriasis and to implicate beta-catenin in the regulation of TGase 1. This evidence suggests a role for beta-catenin signalling in regulating keratinocyte differentiation in interfollicular skin in addition to previously reported functions in stem cell fate determination, hair follicle regulation and skin tumorigenesis.

Weatherhead SC, Wahie S, Reynolds NJ, Meggitt SJ. · Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK. · Br J Dermatol. · Pubmed #17223876 No free full text.

Abstract: BACKGROUND: Treatment options for moderate-to-severe atopic eczema are limited. Although methotrexate (MTX) is a widely used and effective treatment for psoriasis, there have been no previous prospective trials of its use in refractory atopic eczema, despite a few small, retrospective reports suggesting that it is a well-tolerated and effective treatment. OBJECTIVES: We have assessed the safety and efficacy of oral MTX in 12 adults with moderate-to-severe atopic eczema in an open-label, dose-ranging, prospective trial using objective outcome measures. METHODS: All patients had previously received other second-line therapies and had disease only partially responsive to potent topical steroids and emollients. During the 24-week MTX treatment period, unrestricted use of standard topical therapy was permitted. We used an incremental MTX dose regime, starting at 10 mg per week (following a 5-mg test dose) and increasing by 2.5 mg weekly until response was achieved or treatment was limited by toxicity. Disease activity [six area six sign atopic dermatitis (SASSAD) score] was assessed every 4 weeks during treatment and 12 weeks after stopping MTX. The primary endpoint was 24-week change in disease activity. RESULTS: On average, disease activity improved by 52% from baseline (95% confidence interval 45-60%). There were significant improvements in quality of life, body surface area affected and loss of sleep and itch scores. Global response was rated as 'marked improvement' in five of 12 and six of 12 patients, by investigators and patients, respectively. In all patients, the majority of improvement in disease activity was seen by week 12, and, interestingly, patients who had not responded well over this period despite reaching a dose of 15 mg weekly failed to improve with further dose escalation. Only one patient withdrew due to minor adverse effects. MTX was well tolerated by the remaining 11 patients, all of whom completed treatment, achieving a median dose of 15 mg weekly. Importantly, eight of nine patients had a persistent improvement 12 weeks after stopping MTX, with mean disease activity remaining 34% below baseline. CONCLUSIONS: We have shown that MTX is an effective, well-tolerated treatment for moderate-to-severe atopic eczema, and response appears to compare favourably with other second-line therapies. A randomized, controlled trial is now warranted.

McBride SR, Walker P, Reynolds NJ. · Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, U.K. · Br J Dermatol. · Pubmed #14674905 No free full text.

Abstract: BACKGROUND: Recent concerns over the side-effects of psoralen plus ultraviolet (UV) A, immunosuppressive and cytotoxic treatments have led to increased interest in dithranol for treatment of psoriasis. Few studies have investigated how frequently dithranol should be applied. Dithranol-induced inflammation is maximal at 48-72 h, suggesting that daily application of dithranol may not be optimal. OBJECTIVES: To investigate the effectiveness of five times weekly application of short-contact dithranol (SCD) compared with three times weekly application in a dedicated hospital outpatient treatment unit. METHODS: A randomized, within-patient, controlled study was performed. Patients had SCD applied five times weekly to one half of the body, and three times weekly to the other side. Whole-body UVB irradiation was given 5 days a week. Patients were assessed weekly for 8 weeks. Principal outcome measures were percentage reduction in modified Psoriasis Area and Severity Index (mPASI) at the end of study and time to 50% improvement in mPASI score. RESULTS: Twenty-nine patients were recruited; four were excluded from analysis. Mean percentage reduction in mPASI score at the end of study for five times weekly application was 57.3% (95% confidence interval, CI 39.6-75.0%) and for three times weekly application was 55.4% (95% CI 37.8-73.1%; P = 0.34). Mean time to 50% improvement in mPASI for five times weekly treatment was 4.1 weeks and for three times weekly treatment was 4.0 weeks (P = 0.50). There was no difference in the frequency or severity of burning episodes for each side. CONCLUSIONS: This study suggests that three times weekly application of SCD may be as effective as five times weekly when used in conjunction with UVB administered five times weekly. Large studies of whole-body comparisons are warranted to assess further the optimal frequency of SCD and UVB therapy for psoriasis.

Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM. · Department of Dermatology Medical School, Framlington Place, University of Newcastle upon Tyne, NE2 4HH, UK. · Lancet. · Pubmed #11438134 No free full text.

Abstract: BACKGROUND: Narrow-band ultraviolet B (UVB) is an effective treatment for psoriasis, and open studies suggest that this phototherapy might improve atopic eczema. We did a randomised controlled trial to compare narrow-band UVB, UVA, and visible light phototherapy as second-line, adjunctive treatments in adult patients with moderate to severe atopic eczema. METHODS: Phototherapy was administered twice a week for 12 weeks. 26 patients were randomly assigned narrow-band UVB, 24 were assigned UVA, and 23 visible fluorescent light. The primary endpoints were change in total disease activity (sum of scores at six body sites) and change in extent of disease after 24 treatments compared with baseline. Data were analysed by the method of summary measures. FINDINGS: 13 patients withdrew or were excluded from analysis. Mean reductions in total disease activity over 24 treatments in patients who received narrow-band UVB and UVA, respectively, were 9.4 points (95% CI 3.6 to 15.2) and 4.4 points (-1.0 to 9.8) more than in patients who received visible light. Mean reductions in extent of disease after 24 treatments with narrow-band UVB and UVA were 6.7% (1.5 to 11.9) and -1.0% (-5.3 to 3.3) compared with visible light. A small proportion of patients developed erythema after phototherapy or had a flare in their eczema sufficient to withdraw from treatment. INTERPRETATION: Narrow-band UVB is an effective adjunctive treatment for moderate to severe atopic eczema, and the treatment is well tolerated by most patients.

McGill A, Frank A, Emmett N, Turnbull DM, Birch-Machin MA, Reynolds NJ. · Skin and Environmental Interactions Research Group, School of Clinical and Laboratory Sciences, University of Newcastle upon Tyne, UK. · FASEB J. · Pubmed #15802490 links to  free full text

Abstract: Anthralin is a potent topical drug, inducing clearance of psoriatic plaques. Anthralin disrupts mitochondrial function and structure, but its mechanism of action remains undefined. This study aimed to determine whether anthralin induced keratinocyte apoptosis as well as to investigate molecular mechanisms and the role of mitochondria. We studied human keratinocytes and human 143B rho(0) cells, which lack mitochondrial DNA and a functional respiratory chain. We show that anthralin disrupts mitochondrial membrane potential (DeltaPsim) and causes endogenous cytochrome c release, resulting in the activation of caspase-3 and characteristic morphological changes of apoptosis. Disruption of DeltaPsim and cytochrome c release were independent of mitochondrial permeability transition or caspase activation. Human 143B rho(0) cells were resistant to anthralin-induced cell death, disruption of DeltaPsim, and cytochrome c release compared with the isogenic 143B rho+ cell line. Using the intrinsic fluorescence of anthralin, rapid accumulation within mitochondria was observed independent of DeltaPsim. Using assays that measure individual respiratory chain complexes, we show that anthralin specifically interacts with ubiquinone pool. These data indicate that anthralin induces apoptosis through a novel mitochondrial pathway dependent on oxidative respiration and involving electron transfer with the ubiquinone pool. These studies identify keratinocyte apoptosis as a potentially important mechanism involved in the clearance of psoriasis.

Al-Daraji WI, Grant KR, Ryan K, Saxton A, Reynolds NJ. · Department of Dermatology, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. · J Invest Dermatol. · Pubmed #11982754 links to  free full text

Abstract: Systemic cyclosporin A and tacrolimus are effective treatments for psoriasis. Cyclosporin A and tacrolimus block T cell activation by inhibiting the phosphatase calcineurin and preventing translocation from the cytoplasm to the nucleus of the transcription factor nuclear factor of activated T cells (NFAT). Inhibition of T cell activation is thought to account for their therapeutic action in psoriasis. We investigated whether nonimmune cells in human skin express calcineurin and NFAT1 and whether cyclosporin A and tacrolimus block activation of calcineurin/NFAT in epidermal keratinocytes. The expression patterns of the principal components of calcineurin/NFAT signaling pathway in normal human skin and psoriasis were determined by immunohistochemistry. We assessed calcineurin/NFAT activation in cultured keratinocytes by measuring the degree of nuclear localization of calcineurin and NFAT1 using immunofluorescence/confocal microscopy and assessed if cyclosporin A and tacrolimus blocked nuclear translocation of these proteins. A variety of cell types in normal and psoriatic skin expressed calcineurin and NFAT1, but expression was particularly prominent in keratinocytes. The principal cyclosporin A and tacrolimus binding proteins cyclophilin A and FKBP12 were also expressed by keratinocytes and nonimmune cells in skin. NFAT1 was predominantly nuclear in normal basal epidermal keratinocytes. Increased nuclear localization of NFAT1 was observed in suprabasal keratinocytes within lesional and to a lesser extent nonlesional psoriatic epidermis compared to normal skin (p = 0.001 and p = 0.03, respectively), suggesting increased activation of calcineurin in psoriatic epidermal keratinocytes. Agonists that induce keratinocyte differentiation, specifically 12-0-tetradecanoyl-phorbol-13-acetate (TPA) plus ionomycin, TPA, and raised extracellular calcium, induced nuclear translocation of NFAT1 and calcineurin in keratinocytes that was inhibited by pretreatment with cyclosporin A or tacrolimus. In contrast in human dermal fibroblasts, TPA plus ionomycin or TPA did not significantly alter the proportion of nuclear-associated NFAT1. These data provide the first evidence that calcineurin is functionally active in human keratinocytes inducing nuclear translocation of NFAT1 and also indicate that regulation of NFAT1 nuclear translocation in skin is cell type specific. Inhibition of this pathway in epidermal keratinocytes may account, in part, for the therapeutic effect of cyclosporin A and tacrolimus in skin diseases such as psoriasis.

Wahie S, Alexandroff A, Reynolds NJ, Meggit SJ. · No affiliation provided · Br J Dermatol. · Pubmed #16729392 No free full text.

This publication has no abstract.

Wahie S, Alexandroff A, Reynolds NJ. · No affiliation provided · Clin Exp Dermatol. · Pubmed #16681606 No free full text.

This publication has no abstract.