Psoriasis: Barker JN

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.

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Griffiths CE, Barker JN. · Dermatology Centre, Hope Hospital, University of Manchester, Manchester M6 8HD, UK. · Lancet. · Pubmed #17658397 No free full text.

Abstract: Psoriasis, a papulosquamous skin disease, was originally thought of as a disorder primarily of epidermal keratinocytes, but is now recognised as one of the commonest immune-mediated disorders. Tumour necrosis factor alpha, dendritic cells, and T-cells all contribute substantially to its pathogenesis. In early-onset psoriasis (beginning before age 40 years), carriage of HLA-Cw6 and environmental triggers, such as beta-haemolytic streptococcal infections, are major determinants of disease expression. Moreover, at least nine chromosomal psoriasis susceptibility loci have been identified. Several clinical phenotypes of psoriasis are recognised, with chronic plaque (psoriasis vulgaris) accounting for 90% of cases. Comorbidities of psoriasis are attracting interest, and include impairment of quality of life and associated depressive illness, cardiovascular disease, and a seronegative arthritis known as psoriatic arthritis. A more complete understanding of underlying pathomechanisms is leading to new treatments, which will be discussed in the second part of this Series.

Smith CH, Barker JN. · Skin Therapy Research Unit, St Johns Institute of Dermatology, Kings College London, St Thomas' Hospital, London SE1 7EH. · BMJ. · Pubmed #16916825 No free full text.

This publication has no abstract.

Capon F, Trembath RC, Barker JN. · Division of Medical Genetics, Department of Genetics and Cardiovascular Sciences, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK. · Dermatol Clin. · Pubmed #15450331 No free full text.

Abstract: Psoriasis is a complex inflammatory disorder whose pathogenesis is likely to require the contribution of several genes and environmental triggers. Despite the difficulties posed by the study of multifactorial conditions, significant progress has been achieved in relation to the molecular genetic basis of psoriasis. It has long been recognized that the major histocompatibility complex (MHC) region on chromosome 6p21 harbors the main determinant conferring psoriasis susceptibility. The identification of non-MHC susceptibility regions across the genome has been hindered by the likely occurrence of genetic heterogeneity. Nonetheless, evidence for the assignment of a number of non-MHC loci has been achieved through studies, including the collaborative analysis of large patient cohorts, and also through the observation of overlap between psoriasis and atopic dermatitis susceptibility regions.

Bowcock AM, Barker JN. · Department of Genetics, Pediatrics, and Medicine, Washington University School of Medicine, Box 8232, 4566 Scott Avenue, St Louis, MO 63110, USA. · J Am Acad Dermatol. · Pubmed #12894126 No free full text.

Abstract: There is considerable epidemiologic evidence that genes play a key role in the pathogenesis of psoriasis. It is also clear that multiple genes are involved and that the disease is genetically heterogeneous. Important interactions with the environment are also implicated in its development. A number of genetic loci have been identified by genome wide linkage scans and two loci have been replicated: PSORS1 on chromosome 6, within the major histocompatibility complex, and PSORS2 on chromosome 17q. Understanding the genetic basis of psoriasis will represent a major advance in our understanding of the disease and will reveal novel disease-specific biologic pathways. This information will be used to develop more specific diagnostic and prognostic tools and also lead to the development of individualized treatment plans. Benefits of the latter include more effective and safer treatments and potentially major pharmaco-economic gain.

Barker JN. · St John's Institute of Dermatology, St Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK. · Clin Exp Dermatol. · Pubmed #11422183 No free full text.

Abstract: Epidemiological studies indicate that genes play an important role in the pathogenesis of psoriasis. Multiple genes are likely to be involved, interacting not only with each other but also with the environment to cause disease expression. Molecular genetic studies indicate that there are multiple susceptibility loci present throughout the human genome. It is clear that a gene or genes of major impact on psoriasis is present on chromosome 6 within the major histocompatibility complex (MHC). Linkage disequilibrium studies indicate this gene to reside within a 300 kb interval centred around the centromeric end of class I MHC. Known candidate genes in this region are HLA-C, corneodesmosin and HCR, although novel genes, as yet unknown, may also exist. There is accumulating evidence that HLA-C is not itself the causative gene but rather a marker for it. Identification of the genes involved in psoriasis susceptibility will represent a step forward in our understanding of the disease and our future ability to help patients with psoriasis.

Smith CH, Jackson K, Bashir SJ, Perez A, Chew AL, Powell AM, Wain M, Barker JN. · Skin Therapy Research Unit, St John's Institute of Dermatology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK. · Br J Dermatol. · Pubmed #16792769 No free full text.

Abstract: BACKGROUND: Infliximab, a mouse-human chimeric monoclonal antibody directed against tumour necrosis factor-alpha, has been shown to be effective for moderate to severe psoriasis, but there are few data published on its use in recalcitrant, treatment-resistant disease or in combination with other antipsoriatic therapies. OBJECTIVES: To report our experience with infliximab in the treatment of patients attending a tertiary referral service with severe recalcitrant disease. METHODS: All patients attending a tertiary referral service for severe psoriasis who were treated with infliximab between 2002 and July 2005 were entered into a prospective, open-label study. Details on disease phenotype, clinical course and adverse events were recorded together with measures of disease severity [Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index, clinical photography] at baseline, weeks 2 and 6, and then at 2-monthly intervals throughout the treatment period. RESULTS: Twenty-three patients were treated with infliximab during the study; one patient had pustular psoriasis and was therefore excluded from statistical analysis. All had severe disease (baseline PASI 26.5+/-6.7, mean+/-SD, n=22) and had received at least two systemic therapies for psoriasis in the past; 16 were taking one or more concomitant therapies at the time of treatment initiation. At week 10, 95% had achieved a 50% or greater improvement in baseline PASI (PASI 50), and 77% had achieved a 75% or greater improvement (PASI 75). Efficacy was sustained in the longer term, with eight of 10 patients on treatment for more than 11 months maintaining at least a PASI 50. Only one patient had treatment withdrawn due to lack of efficacy, two suffered severe systemic infections including extrapulmonary tuberculosis (splenic abscess) and cellulitis, and six have discontinued due to adverse effects including infusion reactions (two), severe thrombocytopenia (one), hepatitis (one) and malignancy (two). CONCLUSIONS: Data from this open-label study suggest that infliximab is a rapidly effective treatment for patients with severe, treatment-resistant disease, although approximately 25% of patients had to discontinue therapy due to the development of serious adverse effects. Long-term follow-up, continued pharmacovigilance, and further controlled comparative studies will be required to evaluate fully the risks associated with infliximab in the context of this already difficult to treat population.

Bhushan M, Bleiker TO, Ballsdon AE, Allen MH, Sopwith M, Robinson MK, Clarke C, Weller RP, Graham-Brown RA, Keefe M, Barker JN, Griffiths CE. · The Dermatology Centre, Irving Building, University of Manchester, Hope Hospital, Salford, Manchester M6 8HD, UK. · Br J Dermatol. · Pubmed #12000379 No free full text.

Abstract: 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.

Smith CH, Jackson K, Chinn S, Angus K, Barker JN. · Skin Therapy Research Unit, St John's Institute of Dermatology, St Thomas' Hospital, UK. · Clin Exp Dermatol. · Pubmed #11167965 No free full text.

Abstract: Exorex is a new topical formulation for the treatment of psoriasis; it contains 1% coal tar and a synthetic analogue resembling components identified in banana skin (a complex of esterified essential fatty acids). To determine whether the esterified essential fatty acid complex confers any therapeutic advantage over coal tar alone, patients with chronic plaque psoriasis (n = 20) were entered into a double-blind, randomized, right/left comparison of Exorex, and Exorex without the essential fatty acid component (known hereafter as coal tar control) for 8 weeks. Target plaques were scored (0-4) for erythema, desquamation and infiltration at day 0 and at 2 week intervals throughout the study. No significant differences were detected between Exorex and coal tar control with respect to changes in the summed scores at baseline and following 8 weeks of treatment (mean difference in summed score changes from baseline between Exorex and coal tar control 0.2, 95% confidence interval - 0.44 to 0.84; P = 0.52) or in the area under the response-time curve (P = 0.16). Mean percentage improvement in summed scores of target plaques were 53.9% (SE = 4%) and 56.1% (SE = 4.9%) for Exorex and coal tar control, respectively. Results suggest that the complex of esterified essential fatty acids is not exerting any clinically important therapeutic effect in the treatment of chronic plaque psoriasis.

Barker JN, Ashton RE, Marks R, Harris RI, Berth-Jones J. · Skin Therapy Research Unit, St John's Institute of Dermatology, St Thomas' Hospital, London SE1 7EH, UK. · Br J Dermatol. · Pubmed #10468799 No free full text.

Abstract: 1alpha, 25-Dihydroxy-22-oxacalcitriol (maxacalcitol) is a vitamin D3 analogue which displays approximately 10 times greater efficacy at suppressing keratinocyte proliferation in vitro than calcipotriol and tacalcitol. To determine clinical efficacy, a phase II double-blind, randomized, left vs. right, concentration-response study was performed with once-daily topical maxacalcitol in patients with mild to moderate chronic plaque psoriasis. Primary efficacy parameters were psoriasis severity index (PSI) based on sum of scores for erythema, scaling and induration and investigators' overall assessment of patients' response to therapy at 8 weeks of treatment. One hundred and forty-four patients participated. All concentrations of maxacalcitol ointment (6, 12.5, 25 and 50 microg/g) were significantly more effective at reducing PSI than placebo (P < 0.01), with greatest effect noted for maxacalcitol 25 microg/g. Calcipotriol ointment 50 microg/g once daily as active comparator had a similar effect. Marked improvement or clearance of psoriasis was greatest for maxacalcitol 25 microg/g (55% of subjects) which compared favourably with calcipotriol (46%). Improvement continued throughout the study period, with no plateau at week 8. Investigators' and patients' side preference (secondary efficacy parameters) rated maxacalcitol more effective than placebo and 25 microg/g maxacalcitol better than calcipotriol (P < 0.05 for investigators' assessment). Twelve patients withdrew from the study due to adverse events, of which four were judged to be due to study medication. This study indicates that once-daily maxacalcitol ointment is effective in the management of plaque psoriasis, with greatest effect noted at 25 microg/g. As no response plateau was noted at 8 weeks, these data suggest that further benefit might be obtained if maxacalcitol ointment were applied for longer. Finally, investigators' overall assessment and side preference suggest that maxacalcitol 25 microg/g may be more effective than once-daily calcipotriol.

Eedy DJ, Griffiths CE, Chalmers RJ, Ormerod AD, Smith CH, Barker JN, Potter J, Ingham J, Lowe D, Burge S. · Department of Dermatology, Southern Health and Social Care Trust, 68 Lurgan Road, Portadown BT9 6NY, UK. · Br J Dermatol. · Pubmed #19120330 No free full text.

Abstract: BACKGROUND: Medical professionals require data about the structure and delivery of dermatological services in primary and secondary care in order to identify and tackle variations in standards and monitor the impact of healthcare reforms. The British Association of Dermatologists (BAD) commissioned an audit of the provision of care for patients with psoriasis. OBJECTIVES: To assess the staffing and facilities in dermatology units in the U.K. with a focus on the provision of care for patients with psoriasis. METHODS: Data were collected from 100 dermatology units in the U.K. for 1 year using a questionnaire and a web-based collection system. RESULTS: Key results are as follows. Eighteen per cent (18/98) of units had fewer than 2.0 whole-time equivalent consultants and 20% had no specialist dermatology nurse. Only 23% of units collected diagnostic data on outpatients, and half were unable to supply details about the number of attendances for psoriasis. Seventy-seven units reported admitting patients to dedicated dermatology beds, general medical beds, or both; three-quarters of units had access to dedicated adult dermatology beds. Pharmacy services were not always available for dermatology patients. Only 21 units (21%) had dedicated clinics for patients with psoriasis and 56% of units lacked a clinical psychology service willing to accept adult dermatology patients; 59% (55/93) lacked psychological services for children. Fifty-five per cent had no systemic drug monitoring clinic. Phototherapy was run by dermatology nurses in 93% (88/95) of the units and by physiotherapists in 11% (10/94). Biologics for psoriasis were prescribed in 75% (73/97) of units and in 88% (64/73) of these the BAD guidelines for the use of biologics were known to be followed. Of the seventy-three units prescribing biologic therapies, 64% had a nurse trained in the assessment and administration of biologics, 71% had facilities for outpatient infusions (e.g. for infliximab) and 39% were restricted in prescribing biologic agents because of financial constraints. A quality-of-life score was either inadequately or never recorded in outpatient records in 81% of units, increasing to 88% for inpatient records. The Psoriasis Area and Severity Index score was inadequately or never recorded in 79% of outpatient records and 82% of inpatient records. CONCLUSIONS: Units varied in their capacity to meet BAD guidelines and standards. Among the most significant deficiencies identified were a shortage of specialist dermatology nurses, treatment delivery by untrained nurses and financial constraints on the prescription of biologics for psoriasis. Gaps in data collection and record keeping jeopardize efforts to improve standards of care.

Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN, Worthington J, Griffiths CE. · Dermatological Sciences, Salford Royal Hospital, The University of Manchester, Manchester M6 8HD, UK. · Br J Dermatol. · Pubmed #19016697 links to  free full text

Abstract: BACKGROUND: The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug. OBJECTIVES: To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC)] are related to treatment outcomes in patients with psoriasis. METHODS: DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs (r(2) > 0.8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom). RESULTS: There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated. CONCLUSIONS: Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis.

Capon F, Bijlmakers MJ, Wolf N, Quaranta M, Huffmeier U, Allen M, Timms K, Abkevich V, Gutin A, Smith R, Warren RB, Young HS, Worthington J, Burden AD, Griffiths CE, Hayday A, Nestle FO, Reis A, Lanchbury J, Barker JN, Trembath RC. · Division of Genetics and Molecular Medicine, Infection and Inflammatory Disease, King's College London, London, UK. · Hum Mol Genet. · Pubmed #18364390 links to  free full text

Abstract: Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage studies have clearly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), but have generated conflicting results for other genomic regions. To overcome this difficulty, we have carried out a genome-wide association scan, where we analyzed more than 408,000 SNPs in an initial sample of 318 cases and 288 controls. Outside of the MHC, we observed a single cluster of disease-associated markers, spanning 47 kb on chromosome 20q13. The analysis of two replication data sets confirmed this association, with SNP rs495337 yielding a combined P-value of 1.4 x 10(-8) in an overall sample of 2679 cases and 2215 controls. Rs495337 maps to the SPATA2 transcript and is in absolute linkage disequilibrium with five SNPs lying in the adjacent ZNF313 gene (also known as RNF114). Real-time PCR experiments showed that, unlike SPATA2, ZNF313 is abundantly expressed in skin, T-lymphocytes and dendritic cells. Furthermore, an analysis of the expression data available from the Genevar database indicated that rs495337 is associated with increased ZNF313 transcripts levels (P = 0.003), suggesting that the disease susceptibility allele may be a ZNF313 regulatory variant tagged by rs495337. Homology searches indicated that ZNF313 is a paralogue of TRAC-1, an ubiquitin ligase regulating T-cell activation. We performed cell-free assays and confirmed that like TRAC-1, ZNF313 binds ubiquitin via an ubiquitin-interaction motif (UIM). These findings collectively identify a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses.

Smith RL, Warren RB, Eyre S, Ke X, Young HS, Allen M, Strachan D, McArdle W, Gittins MP, Barker JN, Griffiths CE, Worthington J. · arc Epidemiology Unit, The University of Manchester, and Dermatological Sciences, Hope Hospital, Manchester M6 8HD, UK. · Br J Dermatol. · Pubmed #18341666 links to  free full text

Abstract: BACKGROUND: Psoriasis, a chronic inflammatory skin disease, affects approximately 2% of the population worldwide. Although the aetiology of psoriasis is poorly understood, patients with disease of early onset (Type I, age of onset<or=40 years) usually have a strong genetic component to the disease. OBJECTIVES: The purpose of this study was to investigate the role of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene region in susceptibility to Type I psoriasis. PATIENTS AND METHODS: Thirteen single nucleotide polymorphisms (SNPs) mapping to the PTPN22 region were genotyped in 647 patients with Type I psoriasis and 566 normal controls. RESULTS: The rs2476601 (R620W) SNP, widely associated with other inflammatory autoimmune diseases, showed no evidence of association with susceptibility to Type I psoriasis. Two SNPs (rs1217414 and rs3789604) demonstrated significant association with Type I psoriasis and were subsequently genotyped in a further 253 unrelated patients and 2024 normal controls. rs1217414 and rs3789604 were also significantly associated with Type I psoriasis in the combined datasets (P=0.003 and P=0.0002, respectively); furthermore carriage of both risk alleles was also significantly associated (P=0.002). CONCLUSIONS: This study demonstrates evidence of association of two SNPs (rs1217414 and rs3789604) in the PTPN22 region with Type I psoriasis, providing evidence for a role of this gene in Type I psoriasis that is not conferred by the R620W variant previously associated with a number of inflammatory diseases.

Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN, Worthington J, Griffiths CE. · Dermatological Sciences, The University of Manchester, Salford Royal Hospital, Manchester, UK. · J Invest Dermatol. · Pubmed #18256692 links to  free full text

Abstract: Methotrexate, an inexpensive first-line systemic therapy for moderate-to-severe psoriasis, is limited in its use by unpredictable efficacy and toxicity. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in methotrexate transmembrane transporters and adenosine receptors are associated with efficacy and/or toxicity of the drug. DNA was collected from 374 patients with chronic plaque psoriasis who had been treated with methotrexate. Phenotypic data on efficacy and toxicity were available. Haplotype tagging SNPs (r(2)>0.8) across the relevant genes, with a minor allele frequency of >5%, were selected from the HAPMAP phase II data. SNPs within the efflux transporter genes ABCC1 (ATP-binding cassette, subfamily C, member 1) and ABCG2 (ATP-binding cassette, subfamily G, member 2) are associated with good response to methotrexate therapy in patients with psoriasis; the former gene was also associated with the onset of toxicity. With one SNP in ABCC1, rs246240, the carriage of two copies of allele 1 gives an odds ratio of 2.2 (95% confidence interval: 1.3-3.6; P=0.001) for developing toxicity to methotrexate. These data indicate that knowledge of SNPs in genes relevant to methotrexate efflux may be important in selecting patients suitable for this therapy.

White JM, Smith CH, Robson A, Ash G, Barker JN. · Skin Therapy Research Unit, St John's Institute of Dermatology, St Thomas' Hospital, London, UK. · Clin Exp Dermatol. · Pubmed #18021270 No free full text.

Abstract: We report a case of drug reaction with eosinophilia and systemic symptoms (DRESS) to efalizumab. A 52-year-old man developed a widespread papulovesicular rash after 4 weeks of treatment with efalizumab (1.0 mg/kg/week) for treatment-resistant severe psoriasis. Histology revealed a subepidermal blister with eosinophil-rich inflammatory cell infiltrate. Subsequently, the patient developed high peripheral eosinophilia, abnormal liver function, malaise and fever, all requiring inpatient admission. Efalizumab was discontinued immediately, but the rash persisted for 4 months and was only controlled by oral prednisolone at a dose of 30 mg/day. To our knowledge, this is the first reported case of DRESS caused by efalizumab.

Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L, Timms K, Gutin A, Abkevic V, Burden AD, Lanchbury J, Barker JN, Trembath RC, Nestle FO. · Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College, London, UK. · Hum Genet. · Pubmed #17587057 No free full text.

Abstract: Psoriasis is an inflammatory skin disorder that is inherited as a multifactorial trait. Genetic analyses have repeatedly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), on chromosome 6p21. A small number of non-MHC susceptibility loci have also been identified. These regions tend to overlap with susceptibility intervals for Crohn's disease and atopic dermatitis, suggesting the possibility that genetic variants affecting inflammatory pathways may contribute to the pathogenesis of multiple disorders. Here, we report a genetic analysis of the interleukin 23 receptor gene (IL23R), which was recently identified as a susceptibility determinant for Crohn's disease. We initially examined the results of a whole-genome association scan, carried out on 318 cases and 288 controls. We observed a significant increase of a non-synonymous substitution (p.Arg381Gln) among controls (P = 0.00036). We validated this finding by extending our cohort to include a further 519 cases and 528 controls. In the overall sample, the frequency of the 381Gln allele was 3.6% in cases and 7% in controls, yielding a P value of 0.00014. Next, we examined genetic variation at the IL12RB1, IL23A and IL12B genes, respectively, encoding the second subunit of the IL23R receptor and the two subunits of its ligand. This analysis identified independent associations for IL12B SNPs rs10045431 (P value for the extended dataset = 0.0001) and rs3212227 (P = 0.036). Altogether, these findings indicate that genes participating in IL23 signalling play a significant role in the pathogenesis of chronic epithelial inflammation.

Ellis CN, Barker JN, Haig AE, Parker CA, Daly S, Jayawardene DA, Anonymous00172. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA. · Am J Clin Dermatol. · Pubmed #17428114 No free full text.

Abstract: BACKGROUND: Previous research has suggested that the thiazolidinedione rosiglitazone may possess anti-psoriatic activity. OBJECTIVE: To compare the efficacy and safety of rosiglitazone with that of placebo in the treatment of chronic plaque psoriasis. METHODS: Two large-scale, randomized, double-blind, multicenter studies (study A, n = 1563; study B, n = 1032) were conducted over 52 weeks (plus optional 44 weeks safety extension) in an outpatient setting. The subjects (aged 18-75 years) had moderate-to-severe chronic plaque psoriasis affecting >or=10% body surface area (BSA) with plaques of any elevation above normal-appearing skin (or >or=6% BSA involvement with marked elevation) and had not used phototherapy during the previous month or thiazolidinediones within the previous 3 months. Rosiglitazone was administered as 2, 4, or 8 mg tablets once daily. The main outcome measure was the proportion of subjects achieving >or=75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at week 26. RESULTS: Rosiglitazone was well tolerated but no more effective than placebo for moderate-to-severe chronic plaque psoriasis. However, there was a large placebo response unrelated to concomitant rescue medication. Interestingly, subjects had been advised to expect a long period before onset of action. At week 26 and across both studies for subjects receiving placebo, the PASI 75 was 9% (48/506) and the PASI 50 (proportion of subjects who achieved at least 50% improvement from baseline) was 27% (135/506). In addition, few subjects withdrew from placebo or rosiglitazone treatment because of 'lack of efficacy' and the majority persisted in the year-long study. CONCLUSION: While these large-scale, robust studies demonstrated that rosiglitazone is not active in psoriasis, they also showed that for a large proportion of subjects receiving placebo, the expectation of a successful treatment, the favorable adverse effect profile of the drug, and the supportive environment of a clinical study conferred beneficial effects. These results may have implications for the design of future placebo-controlled studies in patients with psoriasis.

Campalani E, Arenas M, Marinaki AM, Lewis CM, Barker JN, Smith CH. · King's College, Skin Therapy Research Unit, St John's Institute of Dermatology, London, UK. · J Invest Dermatol. · Pubmed #17410198 links to  free full text

Abstract: Methotrexate is the gold standard therapy for moderate to severe psoriasis, but there is marked interpersonal variation in its efficacy and toxicity. We hypothesized that in psoriasis patients, specific common polymorphisms in folate, pyrimidine, and purine metabolic enzymes are associated with methotrexate efficacy and/or toxicity. DNA from 203 retrospectively recruited psoriasis patients treated with methotrexate was collected and genotyped by restriction endonuclease digestion or length polymorphism assays. The reduced folate carrier (RFC) 80A allele and the thymidylate synthase (TS) 3'-untranslated region (3'-UTR) 6 bp deletion were associated with methotrexate-induced toxicity (P=0.025 and P=0.025, respectively). RFC 80A and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) 347G were associated with methotrexate discontinuation (P=0.048 and P=0.038). The TS 5'-UTR 28 bp 3R polymorphism correlated with poor clinical outcome (P=0.029), however, this was not the case when patients with palmoplantar pustular psoriasis were not included in the analysis. Stronger associations between specific polymorphisms and methotrexate-induced toxicity and discontinuation were found in a subanalysis of patients on methotrexate not receiving folic acid supplementation. We have demonstrated preliminary evidence that specific polymorphisms of enzymes involved in folate, pyrimidine, and purine metabolism could be useful in predicting clinical response to methotrexate in patients with psoriasis.

Zhao Y, Terron-Kwiatkowski A, Liao H, Lee SP, Allen MH, Hull PR, Campbell LE, Trembath RC, Capon F, Griffiths CE, Burden D, McManus R, Hughes R, Kirby B, Rogers SF, Fitzgerald O, Kane D, Barker JN, Palmer CN, Irvine AD, McLean WH. · Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. · J Invest Dermatol. · Pubmed #17410197 links to  free full text

Abstract: Psoriasis is a common skin disease with an etiology consistent with a multifactorial trait. Several psoriasis susceptibility loci are known, a number of which are also implicated in a predisposition to atopic dermatitis (AD), including the epidermal differentiation complex on chromosome 1q21. It has recently been shown in several replicate studies that prevalent null alleles for the filaggrin gene (FLG) on 1q21 are an important genetic factor in AD. Here, we examined the role of these FLG variants in psoriasis using case:control association studies comparing Irish and UK psoriasis cohorts (combined n=691) to ethnically matched populations (combined n=2117). No association was present for the two common European FLG mutations R501X and 2282del4 (combined chi2 P=0.989). In addition, the 3' end of the FLG open-reading frame was sequenced in a number of patients with differing types of psoriasis (plaque, guttate, palmoplantar, and late-onset), which excluded the possibility of a gain-of-function frameshift mutation such as those found in loricrin or certain keratin genes. These data suggest that FLG mutations are unlikely to be involved in genetic susceptibility to psoriasis and implies that there may be within-locus heterogeneity in chromosomal regions involved in both AD and psoriasis.

Griffiths CE, Christophers E, Barker JN, Chalmers RJ, Chimenti S, Krueger GG, Leonardi C, Menter A, Ortonne JP, Fry L. · Dermatology Centre, The University of Manchester, Hope Hospital, Salford, Manchester, UK · Br J Dermatol. · Pubmed #17223864 No free full text.

Abstract: 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.

Griffiths CE, Finlay AY, Fleming CJ, Barker JN, Mizzi F, Arsonnaud S. · Dermatology Centre, Hope Hospital, University of Manchester, Manchester, UK. · J Dermatolog Treat. · Pubmed #16766333 No free full text.

Abstract: The clinical benefit of currently available tar blend shampoos for the treatment of scalp psoriasis is restricted due to their limited efficacy, low cosmetic appeal and potential for carcinogenicity. This 4-week multicentre, randomized, parallel-group, investigator-masked study included 162 subjects and aimed to compare the efficacy, safety and cosmetic acceptability of clobetasol propionate 0.05% shampoo versus a currently marketed tar blend 1% shampoo in subjects with moderate to severe scalp psoriasis. Clobetasol propionate shampoo was superior to tar blend shampoo with respect to all efficacy variables tested (p<0.001): Total and Global Severity Score; erythema; plaque thickening; desquamation; pruritus; total scalp area involved; and the subject's global assessment of clinical improvement. Both treatments were safe and well-tolerated. Furthermore, more subjects indicated that clobetasol propionate shampoo was more cosmetically acceptable than tar blend shampoo. Clobetasol propionate 0.05% shampoo is a good alternative to tar blend shampoo in the treatment of moderate to severe scalp psoriasis.

Campalani E, Allen MH, Fairhurst D, Young HS, Mendonca CO, Burden AD, Griffiths CE, Crook MA, Barker JN, Smith CH. · The Dermatology Centre, University of Manchester, Hope Hospital, Manchester, UK. · Br J Dermatol. · Pubmed #16433808 No free full text.

Abstract: BACKGROUND: Psoriasis is associated with abnormal plasma lipid metabolism and a high frequency of cardiovascular events. Increased lipid levels are also seen in patients with psoriasis treated with acitretin. Apolipoprotein E (ApoE) variants have been linked to hypertriglyceridaemia and hypercholesterolaemia in normal individuals. Two coding single nucleotide polymorphisms at +3937 and +4075 define the three common ApoE alleles e2, e3 and e4. OBJECTIVES: To test the hypothesis that particular ApoE polymorphism(s) are associated with psoriasis and that specific ApoE allelic variant(s) may be a marker for predicting disease response to acitretin. METHODS: DNA was genotyped for ApoE polymorphisms using a radioactive hybridization technique in cohorts of patients with psoriasis, including patients with chronic plaque psoriasis (CPP, n = 212), guttate psoriasis (GP, n = 94), palmoplantar pustulosis (PPP, n = 101), controls (n = 137), acitretin responders (n =106) and acitretin nonresponders (n = 84). RESULTS: The frequency of the e4 allele (+3937C/+4075C) was significantly higher in patients with CPP and GP than in controls (P = 0.008 and P = 0.02, respectively). There was no significant difference in allele frequencies between patients with PPP and controls. Allelic distribution was similar in acitretin responders and nonresponders. CONCLUSIONS: These data demonstrate an association between the Apo e4 allele and CPP and GP, suggesting a possible pathogenic role for ApoE in psoriasis. Our results do not support a link between disease response to acitretin and the e2, e3 or e4 allelic variants of ApoE.

Young HS, Summers AM, Read IR, Fairhurst DA, Plant DJ, Campalani E, Smith CH, Barker JN, Detmar MJ, Brenchley PE, Griffiths CE. · The Dermatology Centre, The University of Manchester School of Medicine, Hope Hospital, Manchester, UK. · J Invest Dermatol. · Pubmed #16385345 links to  free full text

Abstract: Vascular endothelial growth factor (VEGF) promotes angiogenesis, and elevated levels are found in plaques of psoriasis. Two VEGF polymorphisms, +405 and -460, are associated with early-onset psoriasis and are close to the functional activator protein-1 site (+419) through which retinoids, an established systemic therapy for psoriasis, can block production of VEGF. We report that peripheral blood mononuclear cells (PBMCs) and epidermal keratinocytes (KC) from patients with psoriasis demonstrate differential, genotype-dependent, regulation of VEGF. For PBMCs, VEGF genotype distinguishes two groups of patients with psoriasis - "high and low VEGF producers" (P < 0.001). In contrast, KC production of VEGF is not genotype dependent. However, the effects of all-trans retinoic acid (RA) on cellular expression of VEGF are determined by both cell type and genotype. RA inhibits KC production of VEGF in a genotype-dependent manner (P < 0.005) whereas RA stimulates PBMCs production irrespective of VEGF genotype (P < 0.001). We also report that the -460 VEGF polymorphism appears to have a clinical pharmacogenetic role in predicting response or non-response of psoriasis to acitretin (P = 0.01). In future, determination of VEGF gene polymorphisms and thus individual patient VEGF "signatures" may be used as a prognostic factor for psoriasis susceptibility/severity and as a means for optimizing treatment response.

Ameen M, Allen MH, Fisher SA, Lewis CM, Cuthbert A, Kondeatis E, Vaughan RW, Murakami H, Nakagawa H, Barker JN. · St. John's Institute of Dermatology, Kings College, London, UK. · Clin Exp Dermatol. · Pubmed #15953084 No free full text.

Abstract: PSORS1 on chromosome 6p21.3, which contains the MHC, is a major susceptibility locus for psoriasis vulgaris. This region is characterized by strong linkage disequilibrium and contains the corneodesmosin (CSDN) gene, an attractive candidate for psoriasis susceptibility based on its putative biological function in keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis susceptibility. We compared two genetically independent populations in order to define the major psoriasis susceptibility gene, a British Caucasian population comprising parent-offspring trios analysed by the transmission disequilibrium test (TDT) and a Japanese case-control population. All individuals were investigated for CDSN polymorphism (+619, +1236, +1240 and +1243) and HLA-C association. Our data confirms strong association with HLA-Cw6 and CDSN allele 5 (+619T, +1240G, +1243C) in the Caucasian cohort (TDT, P = 5.4 x 10(-6)) and in addition defines this region further by identifying a high-risk CDSN haplotype (allele 5 and +1236T, P = 8.5 x 10(-8)). In contrast no association was observed in the Japanese cohort for any HLA-C or CDSN alleles. This data supports a role for the CDSN gene in Caucasian populations with psoriasis. However the lack of association with HLA-Cw6 and CDSN alleles in Japanese psoriasis patients may be because Japanese patients exhibit a form of psoriasis similar to late onset or Type II psoriasis vulgaris in contrast to early onset or Type I disease characterizing our Caucasian population.