iTRAQ-based quantitative proteomics reveals biomarkers/pathways in psoriasis that can predict the efficacy of methotrexate.

BACKGROUND: Methotrexate (MTX) is the first-line medicine to treat psoriasis. So far, there has been less research on protein biomarkers to predict its efficacy by the proteomic technique. OBJECTIVES: To evaluate differentially expressed proteins in peripheral mononuclear cells (PBMCs) between good responders (GRs) and non-responders (NRs) after MTX treatment, compared with normal controls (NCs). METHODS: We quantified protein expression of PBMCs with four GRs and four NRs to MTX and four NCs by isobaric tags for relative and absolute quantification (iTRAQ), analysing and identifying proteins related to efficacy of MTX in 18 psoriatic patients. RESULTS: A total of 3177 proteins had quantitative information, and 403 differentially expressed proteins (fold change ≥1.2, P < 0.05) were identified. Compared to NCs, upregulated proteins (ANXA6, RPS27A, EZR, XRCC6), participating in the activation of NF-κB, the JAK-STAT pathway and neutrophil degranulation were detected in GRs. The proteins (GPV, FN1, STOM), involving platelet activation, signalling and aggregation as well as neutrophil degranulation were significantly downregulated in GRs. These proteins returned to normal levels after MTX treatment. Furthermore, Western blotting identified the expression of ANXA6 and STAT1 in PBMCs, which were significantly downregulated in GRs, but not in NRs. CONCLUSIONS: We identified seven differentially expressed and regulated proteins (ANXA6, GPV, FN1, XRCC6, STOM, RPS27A and EZR) as biomarkers to predict MTX efficacy in NF-κB signalling, JAK-STAT pathways, neutrophil degranulation, platelet activation, signalling and aggregation.

TT genotype of rs10036748 in TNIP1 shows better response to methotrexate in a Chinese population: a prospective cohort study.

BACKGROUND: Methotrexate (MTX) is an efficacious treatment for psoriasis; however, its widespread application is limited by its unpredictable efficacy. OBJECTIVES: To investigate the association of clinical factors and variants of psoriasis susceptibility genes with clinical responses to MTX in a prospective cohort. METHODS: A total of 221 patients with psoriasis were recruited. Patients who achieved Psoriasis Area and Severity Index (PASI) improvement ≥ 75% at week 12 were defined as responders, whereas those with PASI improvement < 50% were defined as nonresponders. In 90 screening patients, genetic variants for 18 single-nucleotide polymorphisms in 14 susceptibility genes, and HLA-Cw6 status were initially compared for responders and nonresponders. Statistically significant associations in genetic variants were verified in all 221 patients. RESULTS: Overall, 49% and 45% of patients achieved PASI 75 improvement during screening and verification stages, respectively. Concomitant arthritis with psoriasis and high body mass index (BMI) negatively affect the efficacy of MTX. TT genotype of rs10036748 in TNIP1 was significantly associated with PASI 75 response at week 12 (54% and 37%, P < 0·05). A significantly higher PASI 90 response was observed in patients with TT genotype of rs10036748 (27% vs. 12%, P < 0·01) and TC/TT genotype of rs4112788 in LCE3D (25% vs. 13%, P < 0·05) at week 12 compared with those who had other genotypes. After adjustment for all confounding factors, only BMI (P < 0·05), arthritis (P < 0·05) and genotype of rs10036748 (P < 0·05) were significantly associated with clinical responses to MTX. CONCLUSIONS: Patients with psoriasis with TT genotype of rs10036748 in TNIP1, with lower BMI, without arthritis will achieve a better response to MTX.

IgE and FcεRI are highly expressed on innate cells in psoriasis.

BACKGROUND: Although elevated serum IgE levels have been reported in psoriasis, the role of IgE in psoriasis still needs to be clarified. OBJECTIVES: To analyse serum total IgE levels in addition to the presence and distribution of IgE and FcεRI in psoriatic lesions, and to investigate alteration of IgE and FcεRI after successful systemic treatment. METHODS: Total serum IgE levels were determined using enzyme-linked immunosorbent assay. The expression and localization of IgE and FcεRI was investigated using immunohistochemistry and double immunofluorescence. RESULTS: Elevated total serum IgE levels were found in 39% of patients with psoriasis. The levels of total serum IgE were significantly higher in male patients compared with female patients. Furthermore, total serum IgE levels decreased after successful systemic treatment. A positive correlation between IgE+ and FcεRI+ cells and a significant increase of these cells was found in psoriatic lesions when compared with normal skin. Interestingly, IgE+ and FcεRI+ cells decreased significantly after successful therapy with ustekinumab. IgE and FcεRI were coexpressed on mast cells, epidermal Langerhans cells, dermal dendritic cells, macrophages and a small number of neutrophils. CONCLUSIONS: IgE might participate in the development of psoriasis by activating FcεRI-bearing cells.

Target tissue ectoenzyme CD39/CD73-expressing Foxp3+ regulatory T cells in patients with psoriasis.

BACKGROUND: Psoriasis is a chronic, relapsing, inflammatory skin disease, in which regulatory T cells (Tregs) play an important role. Recently, human Treg ectoenzymes (CD39/CD73) have been reported to mediate the suppressive activity of Tregs. AIM: To investigate the proportions of CD39/CD73 expressing Foxp3(+) regulatory T cells in different types of psoriatic lesions. METHODS: Immunohistochemical staining was used to analyse expression of Foxp3, CD39 and CD73 in biopsy tissue from healthy controls and from patients with different types of psoriasis. RESULTS: In normal control biopsies, CD39(+) cells were scattered throughout the epidermis and dermis, while CD73(+) cells were localized predominantly in the dermis. The proportion of cells that were both CD39(+) and Foxp3(+) was significantly lower in pustular psoriasis (PP) and erythrodermic psoriasis (EP) than in psoriasis vulgaris (PV) (25.0 ± 2.6%, 26.5 ± 2.0% and 45.1 ± 3.5%, respectively; P < 0.001). Likewise, CD73(+) Foxp3(+) cells were lower in PP and EP than in PV (6.2 ± 1.9%, 11.6 ± 2.8% and 17.7 ± 2.3% respectively, P < 0.001). There were no significant differences in the population size of double-staining cells in EP compared with PP. CONCLUSION: The relative reduced expressions of CD39 and CD73 within Foxp3(+) Tregs may imply a different immunopathogenesis for different psoriatic lesions.

A preliminary study of peripheral T-cell subsets in porokeratosis patients with MVK or MVD variants.

Background: Porokeratosis (PK) is considered a skin-specific autoinflammatory keratinization disease. Intriguingly, four causative genes of PK are in turn arranged in mevalonate pathway, with MVD variants being the commonest followed by MVK variants in a cohort of Chinese patients. Evidence indicates that mevalonate metabolites induce trained immunity in human monocytes and regulate T cells at multiple levels. Of note, γδT cells are dually regulated by intracellular and extracellular mevalonate metabolism. Aims: To identify the possible differences in T-cell between MVK or MVD variants from PK patients. Materials & Methods: Targeted exome sequencing and exonic CNV screening were performed in 26 patients with PK. Sanger sequencing was used to validate all identified variants. Among them, 22 patients were identified with MVK or MVD variants. PBMCs from 22 PK patients and 27 normal controls (NCs) were analysed by flow cytometry for the frequencies of T cells subsets, including IFN-γ-, and TNF-α-producing T cells. Results: There were 14 mutations identified in the 26 PK patients, including 6 novel mutations (MVK: c.118_226+1337dup, c.388_392delGATATinsC, c.613A>T, c.768G>C, and MVD: c.250C>T, c.988T>G). In contrast to NCs, significantly decreased frequencies of CD8+ and Vγ9Vδ2 T cells were observed in the PK patients with MVD variants. Moreover, it was found that dysregulated secretion of pro-inflammatory cytokines by T cells in both PK patients with MVK and MVD variants. Conclusions: Our findings enriched the Human Gene Mutation Databases and showed probable differences in peripheral T cells subsets between PK patients and controls.

Foxp3+ regulatory T cells and related cytokines differentially expressed in plaque vs. guttate psoriasis vulgaris.

BACKGROUND: Differences in the number of Foxp3+ regulatory T cells (Tregs) in lesional skin and peripheral blood and their functioning in plaque vs. guttate psoriasis have not been reported. OBJECTIVES: To investigate whether there is a differential expression of Foxp3+ Tregs and a differential regulation of inflammatory cytokines in plaque vs. guttate psoriasis vulgaris. METHODS: The number and the percentage of Foxp3+ cells in different phases of skin lesions of patients with plaque and guttate psoriasis vulgaris were assessed by immunohistochemical staining. The expression of Foxp3 and interleukin (IL)-17 protein in CD4 populations was measured by flow cytometry. Inflammatory cytokine production by transforming growth factor-beta1-induced Foxp3+ Tregs was assessed in an in vitro study. The cytokines in supernatant and serum were determined by enzyme-linked immunosorbent assay. RESULTS: The percentage of Foxp3+ CD3+ cells in the papillary layer was higher than in the reticular layer of dermis and in epidermis (P < 0.05). The numbers of Foxp3+ Tregs in skin lesions and peripheral blood were higher in plaque than in guttate psoriasis, whereas the percentage of IL-17+ CD4+ cells was higher in guttate than in plaque psoriasis (P < 0.05). The numbers of Foxp3+ cells were positively correlated with the Psoriasis Severity Index score of skin lesions (P < 0.0001), and the percentages of Foxp3+ CD4+ cells in peripheral blood were positively correlated with the Psoriasis Area and Severity Index score of patients (P < 0.05). The inhibitory functions of Tregs to IL-17 and IL-6 in guttate psoriasis and to tumour necrosis factor-alpha in plaque psoriasis were deficient. CONCLUSIONS: Differential expression and regulatory functioning for inflammatory cytokine production by Foxp3+ Tregs may imply a different immunopathogenesis for plaque and guttate psoriasis.

Prevalence of anal sex among heterosexuals in California and its relationship to other AIDS risk behaviors.

This paper describes the prevalence of anal sex among heterosexual adults in California and investigates the relationship of anal sex to other risk behaviors associated with AIDS and STDs. The study consisted of telephone interviews with a household probability sample of 3,545 California adults undersampling those age 44 and older. Seven percent of the sexually active respondents, 8% of males, and 6% of females reported having anal sex at least once a month during the year prior to the survey. Of these, most engage in this activity one to five times per month, and about 60% report never using condoms. Younger respondents and those who were not married were more likely to report anal intercourse. Respondents who had anal sex were more likely to report standard AIDS risks and lifestyle risks associated with STDs, and to engage in recreational use of drugs and alcohol. Both anal sex and condom use during anal intercourse were poorly predicted by these demographic and risk variables. It is concluded that a non-trivial proportion of California heterosexual adults engages in anal sex regularly, most without condoms, and those who have anal sex are more likely to have other risk behaviors associated with AIDS and STDs. These results suggest that anal sex must be addressed specifically in clinical and educational programs designed to reduce the spread of AIDS.

AIDS risk behaviours and correlates in teenagers attending sexually transmitted diseases clinics in Los Angeles.

OBJECTIVE: Of all age groups, teenagers have the highest rates of sexually transmitted diseases. Therefore, it is particularly important to target interventions at this group. Teenagers attending STD clinics are at particularly high risk since behaviours that lead to an STD can also result in the transmission of HIV. The goal of this study was to collect information concerning the prevalence and correlates of high-risk behaviours in this population as a first step in the design of an effective intervention programme. METHODOLOGY: Face-to-face interviews were conducted with patients attending five STD clinics operated by the Los Angeles County Department of Health Services. RESULTS: In the exclusively heterosexual teenage subgroup (N = 100, 55% Hispanic, 28% African-American, 10% White), males became sexually active at a younger age than females (14 years vs 14.9 years, p < 0.02), had more partners in the last 12 months (4.1 vs 2.0, p < 0.003), more "steady" partners (2.2 vs 1.4, p < 0.02) and more life time partners (14.1 vs. 4.1, p < 0.001). Only 10.0% of males and 3.8% of females reported consistent condom use with steady partners and 36% of both male and female respondents with non-steady partners. The decision to use condoms during vaginal sex was most likely made by the respondent, whereas the decision not to use condoms was most likely a joint decision. CONCLUSIONS: An intervention aimed at improving sexual communication regarding condom use could increase this behaviour among many adolescents, since only few teenagers in our sample perceived condom use as unpleasant.

Evaluation of an intervention to increase mammography screening in Los Angeles.

METHODS. A randomized pretest post-test control group design was used to evaluate the effectiveness of a mail-out intervention for increasing screening mammography rates. A random sample of 802 women, 40+, residing in Los Angeles County, was surveyed by telephone at baseline and again 12 months after the intervention. RESULTS. Fifty percent of the intervention group and 56% of the control group had obtained a screening mammogram during the follow-up period. This difference was not statistically significant, indicating that the low-cost intervention was not successful in influencing screening mammography rates in this sample. In the combined intervention and control group, a stepwise logistic regression analysis revealed four baseline variables to be significant prospective predictors of mammography behavior during the follow-up period: Women who were adherent to the age-specific screening guidelines at baseline and women who had health insurance were more likely to obtain a mammogram during the follow-up, as were older women. Also, women who were greatly concerned about radiation exposure during a mammogram were about two and a half times less likely to obtain a mammogram during the follow-up than women who were less concerned. Self-reported reasons for adherence and nonadherence to screening guidelines are also described.

Tailored risk notification for women with a family history of breast cancer.

BACKGROUND: Evidence indicates that although first-degree relatives of breast cancer cases are at increased risk of developing the disease themselves, they may be underutilizing screening mammography. Therefore, interventions to increase the use of mammography in this group are urgently needed. METHODS: A randomized two-group design was used to evaluate an intervention to increase mammography use among women (N = 901) with at least one first-degree relative with breast cancer. A statewide cancer registry was used to obtain a random sample of breast cancer cases who identified eligible relatives. The mailed intervention consisted of personalized risk notification and other theoretically driven materials tailored for high-risk women. RESULTS: An overall significant intervention effect was observed (8% intervention group advantage) in mammography at post-test. There was an interaction of the intervention with age such that there was no effect among women <50 years of age and a fairly large (20% advantage) effect among women 50+ and 65+. Health insurance, education, and having had a mammogram in the year before baseline assessment were positive predictors of mammography at post-test. Perceived risk, calculated risk, and relationship to index cancer case were not associated with mammography receipt. CONCLUSION: The intervention was successful in increasing mammography rates among high-risk women 50+ years of age. Further work is needed to determine why it was ineffective among younger women.

AIDS-related attitudes and risk behaviors: a survey of a random sample of California heterosexuals.

BACKGROUND: This paper describes the results of an AIDS knowledge, attitudes, and behaviors survey of a random sample of heterosexual California adults. METHODS: The study was conducted from August 1990 until February 1991 and consisted of telephone interviews conducted in English and Spanish, with a household probability sample of 3,545 California adults, undersampling those age 44 and older. RESULTS: Approximately one-third of the sample believed that HIV/AIDS is contracted by donating blood, and 20% believed the infection could result from insect bites. Tolerance toward HIV-infected persons was highest among young, male, white, employed individuals with higher levels of education and income. Twenty-seven percent of males and 14% of females were categorized as high risk based on the presence of at least 1 of 7 risk factors. High-risk respondents tended to be male, young, employed, never married, U.S. born, and English speaking. Compared to low-risk respondents, they were less likely to use condoms and more likely to use alcohol and drugs in conjunction with sex. Most common sources of AIDS information were television, newspapers, and magazines. CONCLUSIONS: More strenuous efforts are needed to reach young adults, especially those beyond college age, with AIDS prevention messages. Creative messages via popular media venues should be explored.