Patterns of biologic agent utilization among patients with rheumatoid arthritis: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The role of biologic therapies in the treatment of rheumatoid arthritis has expanded, but dosing patterns in the first versus subsequent lines of therapy have not been thoroughly explored.</p> <p>Methods</p> <p>In order to describe patterns of biologic agent utilization among patients with rheumatoid arthritis, health care claims data on use of abatacept, rituximab, or the anti-tumor necrosis factor (TNF) agents etanercept, adalimumab, and infliximab in first- or subsequent-line settings were used to form patient cohorts. Variables included: starting dose (first administration or fill), maintenance dose (third administration or fill), average dose, dose escalation, inter-infusion interval, and discontinuation (gap in therapy > 60 days or switch). Time to discontinuation was assessed with Kaplan-Meier curves and Cox proportional hazards models.</p> <p>Results</p> <p>Over 1 year, average (SD) doses of first-line etanercept (N = 1593; 45.4 [8.8] mg/week), adalimumab (N = 1040; 40.7 [10.4] mg/2 weeks), and abatacept (N = 360; 715.4 [214.5] mg/4 weeks) were similar to the starting and maintenance doses; the average infliximab dose (N = 538; 441.0 [209.2] mg/8 weeks) was greater than the starting and maintenance doses. Trends in the subsequent-line anti-TNF cohorts were similar. The percentages with a dose escalation or discontinuation were greater in the subsequent-line anti-TNF cohorts. The proportion with a dose escalation was greatest for the infliximab cohorts (61.2% first-line and 80.2% subsequent-line). The average period between abatacept infusions was 4.8 [1.4] weeks (4-week approved schedule); and 6.8 [2.6] months between rituximab courses (currently approved schedule is 6 months). Time to discontinuation was significantly shorter for subsequent-line than first-line anti-TNF therapy (median 9.7 vs. 12.5 mo; p < 0.001). The hazard ratio for discontinuing subsequent-line versus first-line anti-TNF therapy was 1.177 (p < 0.001).</p> <p>Conclusions</p> <p>Subsequent-line anti-TNF therapy cohorts had higher rates of discontinuation, dose escalation, and shorter time to discontinuation than first-line anti-TNF cohorts.</p

Transcriptional activation of the alpha 1(I) procollagen gene in systemic sclerosis dermal fibroblasts:. Role of intronic sequences.

OBJECTIVE. To investigate the transcriptional regulation of the alpha 1(I) procollagen gene (COL1A1) in cultured dermal fibroblasts from patients with diffuse systemic sclerosis (SSc) of recent onset and to evaluate the role that intronic sequences may play in the upregulated expression of COL1A1 in SSc dermal fibroblasts. METHODS. Dermal fibroblasts from 6 patients with diffuse SSc of recent onset and from 3 healthy individuals were studied. The steady-state levels of alpha 1(I) procollagen messenger RNA were evaluated by Northern hybridization analysis, and the transcriptional regulation of COL1A1 was examined by transient transfection experiments with deletion constructs containing portions of COL1A1 promoter (with 5\u27 end points at -5.3 kb, -2.3 kb, and -804 bp and 3\u27 end point at +42 bp) ligated to the chloramphenicol acetyltransferase (CAT) reporter gene. To examine the role of intronic sequences, constructs containing, in addition to the COL1A1 promoter, a portion of the first intron (+380 bp to +1,440 bp) cloned in front of the CAT gene were transfected. The efficiency of transfections was normalized relative to the net amount of CAT plasmid actually transfected into recipient cells, determined by a modified Southern hybridization procedure. RESULTS. Maximal CAT activity was observed with constructs extending from -804 bp to +42 bp in both normal and SSc fibroblasts. However, the activity driven by this construct was 80-110% higher in SSc fibroblasts. The CAT activity driven by a construct with a 5\u27 end point at -5.3 kb was only 15-20% higher in SSc cells, and the CAT activity driven by a construct with a 5\u27 end point -2.3 kb was 35-45% higher in SSc fibroblasts. The CAT activity driven by the -804-bp promoter construct was increased up to 4-fold in SSc fibroblasts in comparison with normal cells when the intronic segment spanning +380 bp to +1,440 bp was included in the transfected construct. CONCLUSION. The results directly demonstrate the transcriptional activation of COL1A1 in dermal fibroblasts from SSc patients. The data also indicate that first-intron sequences of COL1A1 are required for maximal transcriptional activity of the collagen gene and may play an important role in the up-regulation of its expression in SSc fibroblasts

Identification of elements in the promoter region of the alpha1(I) procollagen gene involved in its up-regulated expression in systemic sclerosis

OBJECTIVE: To identify regulatory elements in the promoter region of the alpha1(I) procollagen gene (COL1A1) involved in the transcriptional activation of this gene in systemic sclerosis (SSc), and to identify the transcription factors interacting with these regulatory elements. METHODS: Dermal fibroblasts from 6 patients with diffuse SSc of recent onset and from 6 healthy individuals were studied. The transcriptional regulation of COL1A1 was examined by transient transfections with deletion constructs containing portions of the COL1A1 promoter. The DNA binding activity of nuclear proteins recognizing the regulatory regions in the COL1A1 promoter was examined by gel mobility shift assays. A procedure was established to allow the quantitative determination of the amount of DNA binding proteins interacting with the COL1A1 promoter, employing DNA binding protein and DNA titration experiments analyzed by gel mobility shift assays. RESULTS: Maximal chloramphenicol acetyltransferase activity was observed with a -174-bp to +42-bp COL1A1 promoter construct in both normal and SSc cells; however, the activity driven by this construct was 70-260% higher in SSc fibroblasts. Most of the transcriptional activity of the COL1A1 promoter was contained in a minimal promoter region encompassing -174 bp to -84 bp. Electrophoretic mobility shift assays performed with oligonucleotides corresponding to the regions spanning -129/-107 bp and -104/-78 bp of the COL1A1 promoter revealed marked increases in the intensities of DNA-protein complexes formed with both oligonucleotides in nuclear extracts prepared from each of the SSc cell lines in comparison with normal fibroblasts. Competition experiments showed that each of these regions contained elements recognized by Sp1 and nuclear factor 1 (NF-1) binding proteins. A quantitative determination of DNA binding activity recognizing the Sp1 binding element within the -129/-107-bp region showed that it was 23.6 nM in SSc fibroblasts compared with 6.9 nM in normal fibroblasts. CONCLUSION: The results demonstrate that a short region in the proximal promoter of COL1A1 containing 2 tandem NF-1/Sp1 elements displays up-regulated transcriptional activity in SSc fibroblasts, and that SSc fibroblasts contain 3.4-fold greater DNA binding activity recognizing these elements than normal cells