Lentivector-mediated transgenesis is increasingly used, whether for basic studies as an alternative to pronuclear injection of naked DNA or to test candidate gene therapy vectors. In an effort to characterize the genetic features of this approach, we first measured the frequency of germ line transmission of individual proviruses established by infection of fertilized mouse oocytes. Seventy integrants from 11 founder (G0) mice were passed to 111 first generation (G1) pups, for a total of 255 events corresponding to an average rate of transmission of 44%. This implies that integration had most often occurred at the one-or two-cell stage and that the degree of genotypic mosaicism in G0 mice obtained through this approach is generally minimal. Transmission analysis of eight individual proviruses in 13 G2 mice obtained by a G0-G1 cross revealed only 8% of proviral homozygosity, significantly below the 25% expected from purely Mendelian transmission, suggesting counter-selection due to interference with the functions of targeted loci. Mapping of 239 proviral integration sites in 49 founder animals revealed that about 60% resided within annotated genes, with a marked tendency for clustering in the middle of the transcribed region, and that integration was not influenced by the transcriptional orientation. Transcript levels of a set of arbitrarily chosen target genes were significantly higher in two-cell embryos than in embryonic stem cells or adult somatic cells, suggesting that, as previously noted in other settings, lentiviral vectors integrate preferentially into regions of the genome that are transcriptionally active or poised for activation.
ObjectivesTo determine the proportion of patients with psoriatic arthritis in the Adalimumab Effectiveness in Psoriatic Arthritis trial achieving minimal disease activity (MDA) and its individual components at 1 or more visits over 144 weeks, identify baseline predictors of MDA achievement, and evaluate the association of MDA status with independent quality of life (QoL)-related patient-reported outcomes (PROs).MethodsUnivariate and multivariate analyses were used to identify the baseline characteristics that predicted achievement of MDA at individual time points (weeks 12 through 144) or sustained MDA (achievement of MDA at 2 consecutive time points 12 weeks apart). The association of independent QoL-related PROs with MDA achievement was evaluated at weeks 24 and 144.ResultsIn univariate analyses, higher baseline patient assessment of pain, tender joint count (TJC), enthesitis and Health Assessment Questionnaire-Disability Index (HAQ-DI) score were significantly associated with lower likelihood of achieving MDA at later time points. Multivariate analyses confirmed higher baseline HAQ-DI as a significant predictor for failure to achieve MDA at later time points. Achievement of sustained MDA was associated with lower baseline TJC and HAQ-DI score. Achievement of different MDA components appeared to be treatment dependent. MDA achievers had significantly better QoL-related PROs and greater improvements in PROs from baseline to week 24 compared with non-achievers.ConclusionsHigher HAQ-DI score was the most consistent baseline factor that decreased the likelihood of achieving MDA and sustained MDA at later time points. Achieving MDA was associated with better independent QoL-related PROs.
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BackgroundMinimal disease activity (MDA)1 is a clinically meaningful and comprehensive treatment target for psoriatic arthritis (PsA).ObjectivesTo determine if baseline (BL) disease activity and/or patient (pt) demographics predict the ability to achieve MDA at week (wk) 12 in pts with PsA, and to evaluate patient-reported outcomes (PROs) at wk 24 associated with achieving MDA.MethodsData were from the ADEPT (NCT00646386) trial of adalimumab vs placebo in pts with PsA. BL characteristics which predicted achievement of MDA at wk 12 were identified by univariate and multivariate (LASSO) analyses. Continuous variables were age, weight, modified total Sharp score (mTSS), tender/swollen joint count (T/SJC), Pt Global Assessment of disease activity (PtGA) or pain (PtGA-pain), Physician' s Global assessment of disease activity (PhGA), Health Assessment Questionnaire (HAQ), dactylitis, enthesitis (2 sites), Psoriasis Area Severity Index (PASI) and Physician's Global Assessment of Psoriasis (PGAP). Categorical variables were gender, smoking (yes/no), alcohol use (yes/no), methotrexate use (yes/no), rheumatoid factor status, presence/absence of investigator-reported spondylitis, C-reactive protein levels (<2.87 vs ≥2.87), duration of psoriasis/ PsA (<5 or ≥5 years). Pts achieving MDA or not at wk 24 were termed achievers and non-achievers (NA) respectively. PROs assessed at wk 24 were quality of life (QoL) by Dermatology Life Quality Index (DLQI) and Short Form 36 (SF-36) scores (total, physical/ mental component summary (P/MCS), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score. Minimum clinically important differences (MCID) are: DLQI ≥5; SF-36 ≥5; M/PCS ≥2.5; FACIT-F ≥4.ResultsIn the univariate analysis, lower scores at BL for PtGA-pain, SJC66, TJC68, enthesitis and HAQ predicted MDA at wk 12. In the multivariate analysis, a one unit increase in BL HAQ and enthesitis score reduced the odds of achieving MDA at wk 12 by 37.6% and 16.0% respectively. The odds of achieving MDA was reduced by 22.6% for pts with spondylitis at BL compared to pts without spondylitis. At wk 24, MDA achievers (n=27) had significantly better scores (p<0.01) for all PROs than NA (n=98): total SF-36 score (65.3±13.4 vs 41.7±17.0), SF-36 PCS (51.0±7.2 vs. 35.0±10.8), SF-36 MCS (53.2±11.4 vs 45.9±10.7), FACIT-F (43.5±10.6 vs. 30.5±12.2), DLQI (2.1±5.4 vs 6.9±6.8). Achievers had favorable scores at BL already for SF-36 total, PCS and FACIT-F, but not for MCS and DLQI. Achievers had larger changes from BL than NA for all PROs, and reached MCID for all PROs; NA reached MCID only for SF-36 PCS. Age, gender, PsA duration and MTX use did not influence the PROs.ConclusionsAbsence of spondylitis and lower scores for HAQ and enthesitis at BL were found to increase the likelihood of achieving MDA at wk 12. MDA achievement at wk 24 was associated with clinically important improvement in QoL and fatigue.ReferencesCoates et al ARD, 2010; 69: 48-53.AcknowledgementsAbbVie funded the study and participated in design; data collection, analys...
BackgroundIn the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), elevated CRP was shown to predict radiographic progression.1 It is not known if CRP has a predictive role in the clinical response to adalimumab (ADA) treatment; however, it is known that obesity is related to subclinical inflammation as measured by CRP and that psoriatic arthritis (PsA) patients (pts) tend to be obese.ObjectivesTo evaluate the effect of weight (wt) on clinical response in PsA pts treated with ADAMethodsADEPT was a 24-week (wk) double-blind, randomized, placebo-controlled trial in pts with PsA and inadequate response to NSAIDs. In this post hoc analysis, wt was categorized by quartiles (Q). For each wt and CRP category, wk 12 endpoints were analyzed: Clinical Disease Activity Index (CDAI), Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area & Severity Index (PASI) 75 response, and Health Assessment Questionnaire (HAQ). Multivariate analysis was done for wk 12 endpoints accounting for wt quartile and CRP category in the model.Results309/313 pts enrolled had data available. Overall mean wt was 85.8 kg. Wt ranges (kg) per Q were: Q1=45.4–73.0, Q2=73.0–84.4, Q3=85.0–96.2, and Q4=97.0–156.0. CRP was elevated in 242/309 (78.3%). Pts with elevated CRP (%) in each wt Q was: Q1=67.5, Q2=75.3, Q3=85.2, Q4=84.6 (P=0.021). Wt was weakly correlated with CRP at baseline (BL) using non-parametric testing (Kendall Tau b r=0.131, P=0.006). Mean wt was higher in the elevated vs normal CRP group (87.6 kg vs 79.4 kg, P=0.0012). Mean wt (kg) in the elevated CRP group by Q was: Q1=64.6, Q2=78.7, Q3=90.7, Q4=109.7. BL disease activity (tender joint count, swollen joint count, physician and pt global assessment of disease activity, CDAI, PASI, HAQ) was slightly higher in the elevated CRP group. For all outcome measures (CDAI, PsARC (Figure), PASI75, and HAQ) treatment effect was in favor of ADA and no significant difference in treatment effect was observed across wt groups. In pts with both normal (n=67) and elevated (n=242) CRP statistically significant response in favor of ADA was observed for PASI75, with numerically superior but statistically nonsignficant results for CDAI, PsARC, and HAQ in pts with normal CRP. Wt group and CRP were not significant in the multivariate model. For CDAI, PsARC, and HAQ, treatment was statistically significant in favor of ADA regardless of wt or CRP. Sample sizes were too small to make meaningful conclusions for PASI.ConclusionsThe majority of PsA pts in ADEPT had an elevated CRP indicating a general inflammatory state. Overall, ADA-treated pts had superior response rates compared to PBO-treated pts regardless of wt or CRP category. A limitation of this assessment is that wt was used as a surrogate for BMI as pt height was not available.ReferencesGladman DD et al. Arthritis Res Ther. 2010;12:R113.AcknowledgementsAbbVie funded the study (NCT00646386), contributed to its design and was involved in the collection, analysis, and interpretation of the data, and in the writing, review, and approval of th...
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