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Igarashi A.,Nippon Telegraph and Telephone | Kato T.,Janssen Pharmaceutical | Kato M.,Janssen Pharmaceutical | Song M.,Centocor Research and Development Inc. | Nakagawa H.,Jikei University School of Medicine
Journal of Dermatology | Year: 2012

This phase 2/3, double-blind, placebo-controlled study was designed to assess the safety and efficacy of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis. Overall, 158 patients were randomized to receive ustekinumab 45 or 90 mg at weeks 0, 4, and every 12 weeks, or placebo with cross-over to ustekinumab at week 12. The primary end-point was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 12. Physician's Global Assessment (PGA), Dermatology Life Quality Index (DLQI), Nail Psoriasis Severity Index and joint pain Visual Analog Scale (VAS) were also measured. At week 12, 59.4% and 67.7% of ustekinumab 45 and 90 mg patients achieved PASI 75, respectively, compared with 6.5% in the placebo group (P < 0.0001 each). PASI 75 responses were maintained through week 64 in 65.0% and 78.6% of the ustekinumab-treated patients, respectively. Placebo cross-over patients had similar responses to ustekinumab-treated patients. Significant improvements in PGA, DLQI and VAS scores were observed at week 12 and generally maintained over time. Adverse events during the placebo-controlled period were similar among groups (45 mg, 65.6%; 90 mg, 59.7%; placebo, 65.6%). Serious adverse events were observed in 0%, 4.8% and 6.3% of patients, respectively. Through week 72, similar rates and types of adverse events and serious adverse events were reported in patients receiving 45 and 90 mg. Rates of injection site reactions and antibodies to ustekinumab were low. Ustekinumab was efficacious and generally well-tolerated in Japanese patients with moderate-to-severe plaque-type psoriasis through 72 weeks. These results are consistent with those reported in the global, phase 3 studies. © 2011 Japanese Dermatological Association. Source

Sonnenberg G.F.,University of Pennsylvania | Monticelli L.A.,University of Pennsylvania | Elloso M.M.,Centocor Research and Development Inc. | Fouser L.A.,Pfizer | Artis D.,University of Pennsylvania
Immunity | Year: 2011

Fetal CD4+ lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that after infection with Citrobacter rodentium, CD4+ LTi cells were a dominant source of interleukin-22 (IL-22) early during infection. Infection-induced CD4+ LTi cell responses were IL-23 dependent, and ablation of IL-23 impaired innate immunity. Further, depletion of CD4+ LTi cells abrogated infection-induced expression of IL-22 and antimicrobial peptides, resulting in exacerbated host mortality. LTi cells were also found to be essential for host protective immunity in lymphocyte-replete hosts. Collectively these data demonstrate that adult CD4+ LTi cells are a critical source of IL-22 and identify a previously unrecognized function for CD4+ LTi cells in promoting innate immunity in the intestine. © 2011 Elsevier Inc. Source

Schoels M.,Hietzing Hospital | Aletaha D.,Medical University of Vienna | Funovits J.,Medical University of Vienna | Kavanaugh A.,University of California at San Diego | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Background and objectives: Instruments for measuring disease activity in psoriatic arthritis (PsA) are not yet firmly established, and most of the currently employed ones have been derived for rheumatoid arthritis. Some of these instruments are based on 28 joint counts, which do not capture joints frequently affected in PsA. Therefore, the reliability and validity of DAREA (for 'Disease Activity index for REactive Arthritis'), which was originally developed for reactive arthritis and employs a 66/68 joint count, was tested in patients with PsA. Methods: Trial data from the Infliximab Multinational Psoriatic Arthritis Controlled Trial were analysed. Results were then independently validated using an observational data set. DAREA was compared to other composite indices regarding correlations with core set variables, sensitivity to change and criterion validity. Results: Good correlation of the DAREA with single items of disease activity, other composite scores (r=0.6-0.9) and physical function (Health Assessment Questionnaire; r=0.5) was found. Likewise, DAREA was at least as sensitive to change as the other indices and more so in patients with distal interphalangeal joint involvement. Additionally, DAREA correlated well with radiographic changes. Conclusion: The analyses of this study provide evidence of the utility and validity of the DAREA for PsA disease activity assessment. A second name should therefore be assigned to this score: DAPSA (for 'Disease Activity index for PSoriatic Arthritis'). Source

Boland B.,University College Dublin | Boland B.,University of Oxford | Smith D.A.,University of Oxford | Mooney D.,University College Dublin | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

Alterations in the metabolism of amyloid precursor protein (APP) are believed to play a central role in Alzheimer disease pathogenesis. Burgeoning data indicate that APP is proteolytically processed in endosomal-autophagic- lysosomal compartments. In this study, we used both in vivo and in vitro paradigms to determine whether alterations in macroautophagy affect APP metabolism. Three mouse models of glycosphingolipid storage diseases, namely Niemann-Pick type C1, GM1 gangliosidosis, and Sandhoff disease, had mTOR-independent increases in the autophagic vacuole (AV)-associated protein, LC3-II, indicative of impaired lysosomal flux. APP C-terminal fragments (APPCTFs) were also increased in brains of the three mouse models; however, discrepancies between LC3-II and APP-CTFs were seen between primary (GM1 gangliosidosis and Sandhoff disease) and secondary (Niemann-Pick type C1) lysosomal storage models. APP-CTFs were proportionately higher than LC3-II in cerebellar regions of GM1 gangliosidosis and Sandhoff disease, although LC3-II increased before APP-CTFs in brains of NPC1 mice. Endogenous murine Aβ40 from RIPA-soluble extracts was increased in brains of all three mice. The in vivo relationship between AV and APP-CTF accumulation was also seen in cultured neurons treated with agents that impair primary (chloroquine and leupeptin + pepstatin) and secondary (U18666A and vinblastine) lysosomal flux. However, Aβ secretion was unaffected by agents that induced autophagy (rapamycin) or impaired AV clearance, and LC3-II-positive AVs predominantly co-localized with degradative LAMP-1-positive lysosomes. These data suggest that neuronal macroautophagy does not directly regulate APP metabolism but highlights the important anti-amyloidogenic role of lysosomal proteolysis in post-secretase APP-CTF catabolism. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Lebwohl M.,Mount Sinai School of Medicine | Papp K.,University of Western Ontario | Han C.,Johnson and Johnson Pharmaceutical Services LLC | Schenkel B.,Johnson and Johnson Pharmaceutical Services LLC | And 3 more authors.
British Journal of Dermatology | Year: 2010

Background PHOENIX 1 was a phase III, randomized, double-blind, placebo-controlled study that demonstrated the long-term efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis. Objectives To assess the effect of ustekinumab maintenance therapy on health-related quality of life (HRQoL) in PHOENIX 1 patients. Patients and methods Patients (n = 766) were randomized to receive ustekinumab 45 mg (n = 255) or 90 mg (n = 256) at weeks 0 and 4 and every 12 weeks thereafter, or placebo (n = 255) at weeks 0 and 4 with crossover to ustekinumab at week 12. Ustekinumab-randomized patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI) 75 at weeks 28 and 40 were re-randomized at week 40 to continue ustekinumab or be withdrawn until loss of therapeutic effect. HRQoL was assessed using the SF-36 and Dermatology Life Quality Index (DLQI). Results At baseline, more than 97% had a DLQI > 1 and the average DLQI was > 10, indicating a significant impact on patients' HRQoL. Significantly greater proportions of patients receiving ustekinumab 45 and 90 mg achieved a normalized DLQI score (≤ 1) compared with placebo (53·2%, 52·4% and 6·0%, respectively, both P < 0·001) at week 12 and achieved a clinically meaningful improvement (increase of at least five points) in SF-36 physical (23·1%, 33·7% and 15·6%) and mental (25·5%, 31·3% and 14·8%) component summary scores. At week 12, changes in individual DLQI and SF-36 domains were significantly better in each ustekinumab group vs. placebo (P < 0·001). The magnitude of improvement across SF-36 scales was greatest for the bodily pain and social functioning domains. Improvements in HRQoL were sustained with maintenance ustekinumab therapy through at least 1 year. Regression analysis showed that, after adjustment for improvement in PASI or Physician's Global Assessment (PGA), ustekinumab-treated patients demonstrated significant improvements in DLQI. Conclusions Ustekinumab improves HRQoL in patients with moderate-to-severe psoriasis. Patient-reported outcomes measured a treatment effect beyond that indicated by clinical measures. © 2009 British Association of Dermatologists. Source

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