This study correlated assessment tools for evaluating the severity of skin, nail, and joint symptoms in patients with psoriasis (Pso) and psoriatic arthritis (PsA). Adults with plaque Pso (with or ...without PsA) were enrolled from four U.S. institutions. Patients were evaluated using a novel 10-area Linear Psoriasis Area and Severity Index (XL-PASI), Psoriatic Arthritis Assessment (PsAA), Psoriatic Arthritis Screening and Evaluation Questionnaire (PASE), Nail Assessment (NA) and Joint Assessment (JA) tools, Psoriasis Weighted Extent and Severity Index (PWESI), and Lattice Physician Global Assessment (LS-PGA). Correlations between assessment tools and individual items in the assessment tools were performed. Data from 180 patients (55 with PsA) were analyzed. Highest correlations between tools (r = 0.77-0.88) were between the XL-PASI, PWESI and LS-PGA. Individual items in the XL-PASI correlated with items in the PWESI for extent skin symptoms, but not for all body areas. Overall, correlations were seen between hands and feet, between face and scalp, and between buttocks, chest, and back. Only low correlation was seen between items assessing joint symptoms with items assessing skin symptoms. These data support the notion that the complex phenotype of psoriatic disease requires instruments that assess the severity of skin, nails, and joints separately.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 CTLA-4), provides a pivotal ...costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.
Summary
Background Type 1 T cells are hypothesized to be central in the immunopathogenesis of psoriasis. Through elaboration of interferon (IFN)‐γ, type 1 T cells regulate the expression of many ...‘downstream’ inflammatory genes, including an array of chemokines that regulate leucocyte trafficking and activation in skin lesions. Accordingly, disease progression and/or severity might be controlled by the degree to which differing cytokines and chemokines are overexpressed in focal skin regions. To examine this possibility, we studied two forms of chronic psoriasis vulgaris that differ significantly in overall severity and progression: small plaque (SP) psoriasis occurring in Korean patients, and large plaque (LP) psoriasis occurring in North American patients.
Objectives To characterize LP and SP psoriasis vulgaris with respect to expression of proinflammatory genes that define the type 1 T‐cell axis in skin lesions genes encoding interleukin (IL)‐12, IFN‐γ, and IFN‐γ‐regulated chemokines or inflammatory mediators.
Methods Total cellular RNA of skin samples from groups of patients with LP or SP psoriasis was analysed by quantitative reverse transcription‐polymerase chain reaction (TaqMan analysis) to compare the differences in mRNA expression of genes related to the IFN‐γ pathway.
Results The mRNA expression of keratin 16, CD25, IFN‐γ, IL‐12 p40, signal transducer and activator of transcription‐1, inducible nitric oxide synthase, IL‐8, macrophage inflammatory protein‐3α, monocyte chemoattractant protein‐1, S100A12, IFN‐γ‐inducible protein of 10 kDa, IFN‐inducible T‐cell α‐chemoattractant and monokine induced by IFN‐γ was increased in the lesions of both LP psoriasis and SP psoriasis. However, IL‐18 mRNA expression was significantly different in the lesions of LP psoriasis in comparison with those of SP psoriasis.
Conclusions The results indicate that proinflammatory type 1 genes regulated by IFN‐γ are similarly increased in both SP and LP psoriasis, but a potential difference in IL‐18 exists between these disease forms. The consistent activation of this set of genes argues for a central role of IFN‐γ as a molecular regulator of inflammation in these distinct subtypes of psoriasis vulgaris. In contrast, disease extent/severity must be controlled by yet other factors.
Two high‐resolution, general‐purpose, small‐angle neutron scattering instruments have been constructed at the National Institute of Standards and Technology's Center for Neutron Research. The ...instruments are 30 m long and utilize mechanical velocity selectors, pinhole collimation and high‐data‐rate two‐dimensional position‐sensitive neutron detectors. The incident wavelength, wavelength resolution and effective length of the instruments are independently variable, under computer control, and provide considerable flexibility in optimizing beam intensity and resolution. The measurement range of the instruments extends from 0.0015 to 0.6 Å−1 in scattering wavevector, corresponding to structure in materials from 10 Å to nearly 4000 Å. The design and characteristics of the instruments, and their modes of operation, are described, and data are presented which demonstrate their performance.
Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Psoriasis is currently thought of as a ...T-cell mediated 'Type-1' autoimmune disease. Gene expression changes in psoriasis lesions have been well documented, and strongly support an important role for tumor necrosis factor and interferon gamma signal pathways in its pathogenesis. The strongest genetic determinant of psoriasis identified to date lies within the class I region of the multiple histocompatibility locus antigen cluster, although its low penetrance implicates a requirement for other genetic risk factors. Multiple genome-wide linkage and an increasing number of association studies have been carried out, leading to multiple linkage peaks, and the identification of potential low risk variants. A number of these variants lie within genes encoding components of the immune system. However, the functional relationships between predisposing genetic variation is unclear, and presumably involves genetic susceptibility factors affecting both immune cell activation and keratinocyte differentiation. The interaction of environmental trigger factors with genetic effects is also not understood, but provide further evidence for the complex basis of this disease.
Psoriasis is now classified as an immune-mediated inflammatory disease (IMID) of the skin. It is being recognized that patients with various IMIDs, including psoriasis, are at higher risk of ...developing “systemic” co-morbidities, e.g., cardiovascular disease (CVD), metabolic syndrome, and overt diabetes. In non-psoriatic individuals, the pathophysiology of obesity, aberrant adipocyte metabolism, diabetes, and CVDs involves immune-mediated or inflammatory pathways. IMIDs may impact these co-morbid conditions through shared genetic risks, common environmental factors, or common inflammatory pathways that are co-expressed in IMIDs and target organs. Given that pathogenic immune pathways in psoriasis are now well worked out and a large number of inflammatory mediators have been identified in skin lesions, in this review we will consider possible mechanistic links between skin inflammation and increased risks of (1) obesity or metabolic alterations and (2) CVD. In particular, we will discuss how well-established risk factors for CVD can originate from inflammation in other tissues.
Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting ∼2% of the Western population. It occurs more frequently in individuals with human immunodeficiency ...virus, and 20–30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, and previous linkage analysis by our group identified a second psoriasis locus at 17q24–q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets. Additional loci have also been proposed to be associated with psoriasis. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain–containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A series of experiments was conducted to identify the molecular species responsible for surface active emulsification (surfactant) bioactivity in Bacillus subtilis subsp. subtilis strain ATCC ...PTA‐125135, and to describe culture conditions to support the enriched production of said bioactivity in cultured plaque of the strain. The assay for methylene blue active substances (MBAS) was found to be suitable for describing surfactant activity, where a solvent‐extracted molecular fraction from the biofilm was found to retain surfactant activity and positively quantified as MBAS. Furthermore, an HPLC‐refined protein fraction was found to quantify as MBAS with approximately 1·36‐fold or greater surfactant activity per mol than sodium dodecyl sulphate, and a proteomic analysis of solvent extracted residues confirmed that biofilm surface layer protein BslA was a primary constituent of extracted residues. Surfactant bioactivity, quantified as MBAS, was enriched in cultured plaque by the supplementation of culture media with calcium chloride or calcium nitrate.
Significance and Impact of the Study: Surfactants with emulsifying bioactivity are known to be produced by Bacillus subtilis. Here, a colorimetric assay for methylene blue active substances is adapted for use in bacterial plaque to describe surfactant bioactivity, and supplemental salts of calcium during culture are shown to enrich cultured plaque for said bioactivity. Where B. subtilis is utilized as a feed additive to food producing animals, the manufacture of bacterial plaque with controlled and enriched concentration of surfactant bioactivity is desirable, especially where the dose amount is limited by mass, total colony forming units, enzymatic activities or other limiting qualities.
ABSTRACT
Objective: To evaluate the clinical and biological activity of apremilast in patients with severe plaque-type psoriasis.
Research design and methods: Apremilast, a phosphodiesterase‑4 ...inhibitor, inhibits in vitro activity of multiple inflammatory factors implicated in the pathogenesis of psoriasis. Patients received 20 mg apremilast orally for 29 days. Immunohistological analysis was conducted on lesional-skin biopsies for psoriasis-associated inflammatory markers. Lipopolysaccharide-stimulated tumor necrosis factor‑α levels were evaluated in blood. Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment, and Body Surface Area were used to monitor disease severity.
Results: There were 19 patients enrolled in this study, of whom 17 completed the study. Epidermal thickness was reduced by a mean of 20.5% from baseline to day 29. Among the responders, T cells were reduced by 28.8% and 42.6% in the dermis and epidermis, respectively. Similarly, CD11c cells were reduced by 18.5% and 40.2% in the dermis and epidermis, respectively. Fourteen of the 19 (73.7%) patients demonstrated an improvement in their PASI scores.
Limitations: This was a small, single-arm, open-label pilot study; therefore there was neither a placebo nor a comparison group.
Conclusion: Apremilast demonstrated biological activity and improved psoriasis clinical efficacy scores in patients with severe plaque-type psoriasis. The majority of adverse events were mild in nature. Two adverse events (fatigue and dizziness) were judged by the investigator to be moderate and related to apremilast. In addition, there were no clinically-relevant abnormal laboratory test results in subjects treated with apremilast for 29 days.
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