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Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis.

Chakravarty EF, Martyanov V, Fiorentino D, Wood TA, Haddon DJ, Jarrell JA, Utz PJ, Genovese MC, Whitfield ML, Chung L - Arthritis Res. Ther. (2015)

Bottom Line: Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline.After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114).Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action.

View Article: PubMed Central - PubMed

Affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. Eliza-Chakravarty@omrf.org.

ABSTRACT

Introduction: Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.

Methods: Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.

Results: Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.

Conclusions: Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.

Trial registration: ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

No MeSH data available.


Related in: MedlinePlus

CD28 pathway trends across abatacept improver and non-improver samples. a Expression of 19 genes contributing the most to the GSEA enrichment score (core enrichment group) is shown in improvers. Genes are ordered by the GSEA rank metric score with those contributing the most to the enrichment score at the top and those contributing the least at the bottom. Array tree is from Fig. 1a. b CD28 pathway trends across improver and non-improver baseline (base) and post-treatment (post) samples. Expression values are for centroid vectors generated by averaging expression data for each of 19 genes across all respective samples (e.g., all improver bases). p-values are for paired (base vs. post) and unpaired (base vs. base) t-test comparisons. Graphs show mean with SD scatter plots
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Fig3: CD28 pathway trends across abatacept improver and non-improver samples. a Expression of 19 genes contributing the most to the GSEA enrichment score (core enrichment group) is shown in improvers. Genes are ordered by the GSEA rank metric score with those contributing the most to the enrichment score at the top and those contributing the least at the bottom. Array tree is from Fig. 1a. b CD28 pathway trends across improver and non-improver baseline (base) and post-treatment (post) samples. Expression values are for centroid vectors generated by averaging expression data for each of 19 genes across all respective samples (e.g., all improver bases). p-values are for paired (base vs. post) and unpaired (base vs. base) t-test comparisons. Graphs show mean with SD scatter plots

Mentions: Since the mechanism of action of abatacept is to prevent the CD28-dependent co-stimulatory activation of T cells by binding to the CD80 and CD86 on antigen-presenting cells (APCs), we tested the hypothesis that we would observe a decrease in the expression of genes associated with T cell activation, specifically CD28-dependent signaling. We found that the Reactome molecular pathway, costimulation by the CD28 family, was significantly decreased post-treatment in abatacept improvers (FDR 7.7 %). This pathway comprises genes responsible for signaling events downstream of the CD28 superfamily of receptors that are required for the activation of T lymphocytes (in conjunction with the T cell receptor complex). Figure 3a shows 19 genes annotated to the CD28 pathway in Reactome that were the most significant contributors to the GSEA enrichment results. These genes were significantly upregulated in improvers versus non-improver at baseline (p < 0.01) and significantly downregulated in improvers post-treatment (p < 0.0001) suggesting the specific inhibition of CD28 co-stimulatory signals by abatacept therapy in improvers as opposed to the non-improver (Fig. 3b).Fig. 3


Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis.

Chakravarty EF, Martyanov V, Fiorentino D, Wood TA, Haddon DJ, Jarrell JA, Utz PJ, Genovese MC, Whitfield ML, Chung L - Arthritis Res. Ther. (2015)

CD28 pathway trends across abatacept improver and non-improver samples. a Expression of 19 genes contributing the most to the GSEA enrichment score (core enrichment group) is shown in improvers. Genes are ordered by the GSEA rank metric score with those contributing the most to the enrichment score at the top and those contributing the least at the bottom. Array tree is from Fig. 1a. b CD28 pathway trends across improver and non-improver baseline (base) and post-treatment (post) samples. Expression values are for centroid vectors generated by averaging expression data for each of 19 genes across all respective samples (e.g., all improver bases). p-values are for paired (base vs. post) and unpaired (base vs. base) t-test comparisons. Graphs show mean with SD scatter plots
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487200&req=5

Fig3: CD28 pathway trends across abatacept improver and non-improver samples. a Expression of 19 genes contributing the most to the GSEA enrichment score (core enrichment group) is shown in improvers. Genes are ordered by the GSEA rank metric score with those contributing the most to the enrichment score at the top and those contributing the least at the bottom. Array tree is from Fig. 1a. b CD28 pathway trends across improver and non-improver baseline (base) and post-treatment (post) samples. Expression values are for centroid vectors generated by averaging expression data for each of 19 genes across all respective samples (e.g., all improver bases). p-values are for paired (base vs. post) and unpaired (base vs. base) t-test comparisons. Graphs show mean with SD scatter plots
Mentions: Since the mechanism of action of abatacept is to prevent the CD28-dependent co-stimulatory activation of T cells by binding to the CD80 and CD86 on antigen-presenting cells (APCs), we tested the hypothesis that we would observe a decrease in the expression of genes associated with T cell activation, specifically CD28-dependent signaling. We found that the Reactome molecular pathway, costimulation by the CD28 family, was significantly decreased post-treatment in abatacept improvers (FDR 7.7 %). This pathway comprises genes responsible for signaling events downstream of the CD28 superfamily of receptors that are required for the activation of T lymphocytes (in conjunction with the T cell receptor complex). Figure 3a shows 19 genes annotated to the CD28 pathway in Reactome that were the most significant contributors to the GSEA enrichment results. These genes were significantly upregulated in improvers versus non-improver at baseline (p < 0.01) and significantly downregulated in improvers post-treatment (p < 0.0001) suggesting the specific inhibition of CD28 co-stimulatory signals by abatacept therapy in improvers as opposed to the non-improver (Fig. 3b).Fig. 3

Bottom Line: Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline.After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114).Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action.

View Article: PubMed Central - PubMed

Affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. Eliza-Chakravarty@omrf.org.

ABSTRACT

Introduction: Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.

Methods: Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.

Results: Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.

Conclusions: Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.

Trial registration: ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

No MeSH data available.


Related in: MedlinePlus