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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

Gene and pathway signatures between abatacept and placebo groups post-treatment. a Blue identifiers are improvers, black identifiers are placebos and orange identifier is non-improver; b 1,354 genes were significantly differentially expressed between abatacept and placebo groups post-treatment (p < 0.05); c 63 pathways had significant differential expression between abatacept and placebo groups post-treatment (FDR <10 %)
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Fig5: Gene and pathway signatures between abatacept and placebo groups post-treatment. a Blue identifiers are improvers, black identifiers are placebos and orange identifier is non-improver; b 1,354 genes were significantly differentially expressed between abatacept and placebo groups post-treatment (p < 0.05); c 63 pathways had significant differential expression between abatacept and placebo groups post-treatment (FDR <10 %)

Mentions: We identified 1,354 genes significantly differentially expressed (p < 0.05, unpaired t-test) between abatacept and placebo patients post-treatment (Fig. 5a). Of the genes upregulated in abatacept post-treatment samples, 801 were enriched in cell cycle, chromosome segregation and nuclear division (FDR <5 %), while 553 genes with the increased expression in placebo post-treatment samples were enriched in cell proliferation, inflammatory response, cytokine production and immune system process (FDR <5 %) (Fig. 5b). GSEA identified 63 pathways with significant differential expression between abatacept and placebo samples (FDR <10 %); 53 pathways increased in the abatacept group post-treatment were related to cell cycle (e.g., G2/M checkpoints, meiosis, DNA replication, Aurora B signaling and PLK1 signaling) whereas 10 pathways upregulated in placebo post-treatment samples were related to the immune response (e.g., Th1/Th2 differentiation, IL12 signaling and cytokine-cytokine receptor interaction) (Fig. 5c). These results suggest that abatacept-treated patients lost inflammatory signature whereas placebo-treated patients became more inflammatory post-treatment.Fig. 5


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)

Gene and pathway signatures between abatacept and placebo groups post-treatment. a Blue identifiers are improvers, black identifiers are placebos and orange identifier is non-improver; b 1,354 genes were significantly differentially expressed between abatacept and placebo groups post-treatment (p < 0.05); c 63 pathways had significant differential expression between abatacept and placebo groups post-treatment (FDR <10 %)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Gene and pathway signatures between abatacept and placebo groups post-treatment. a Blue identifiers are improvers, black identifiers are placebos and orange identifier is non-improver; b 1,354 genes were significantly differentially expressed between abatacept and placebo groups post-treatment (p < 0.05); c 63 pathways had significant differential expression between abatacept and placebo groups post-treatment (FDR <10 %)
Mentions: We identified 1,354 genes significantly differentially expressed (p < 0.05, unpaired t-test) between abatacept and placebo patients post-treatment (Fig. 5a). Of the genes upregulated in abatacept post-treatment samples, 801 were enriched in cell cycle, chromosome segregation and nuclear division (FDR <5 %), while 553 genes with the increased expression in placebo post-treatment samples were enriched in cell proliferation, inflammatory response, cytokine production and immune system process (FDR <5 %) (Fig. 5b). GSEA identified 63 pathways with significant differential expression between abatacept and placebo samples (FDR <10 %); 53 pathways increased in the abatacept group post-treatment were related to cell cycle (e.g., G2/M checkpoints, meiosis, DNA replication, Aurora B signaling and PLK1 signaling) whereas 10 pathways upregulated in placebo post-treatment samples were related to the immune response (e.g., Th1/Th2 differentiation, IL12 signaling and cytokine-cytokine receptor interaction) (Fig. 5c). These results suggest that abatacept-treated patients lost inflammatory signature whereas placebo-treated patients became more inflammatory post-treatment.Fig. 5

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