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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 in abatacept improvers. a Blue identifiers designate baseline and black identifiers designate post-treatment samples; b 398 genes showed significant differential expression (p < 0.05) between baseline and post-treatment improver samples during the course of abatacept treatment; c 133 pathways were significantly differentially expressed in improvers (FDR <10 %). Color bar here and on subsequent figures represents single sample Gene Set Enrichment Analysis Normalized Enrichment Score (ssGSEA NES)
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Fig2: Gene and pathway signatures in abatacept improvers. a Blue identifiers designate baseline and black identifiers designate post-treatment samples; b 398 genes showed significant differential expression (p < 0.05) between baseline and post-treatment improver samples during the course of abatacept treatment; c 133 pathways were significantly differentially expressed in improvers (FDR <10 %). Color bar here and on subsequent figures represents single sample Gene Set Enrichment Analysis Normalized Enrichment Score (ssGSEA NES)

Mentions: We identified 398 genes as significantly differentially expressed (p < 0.05, paired t-test) between baseline and post-treatment in the improvers (Fig. 2a). Genes with increased expression in improvers post-treatment included genes associated with general cell growth and cell cycle-related processes such as DNA repair (POLE, SWI5 and RAD52), microtubule cytoskeleton (DOCK7) and mRNA processing (CDK12). Genes with decreased expression in improvers post-treatment included genes associated with immune activation (e.g., T cell proliferation, T cell costimulation, inflammasome) and included chemokine ligands and receptors (CCL7, CCL2 and CXCR6), adhesion molecules (VCAM1, BCAM), T cell co-stimulator molecules (ICOS, ICOSLG), complement components (C3, C1S) and other genes known to play a role in the immune system (Fig. 2b). This subset of the improver gene signature (188 genes) was significantly enriched (FDR <5 %) in several immune system-related terms (e.g., immune system process, immune response, cell activation and leukocyte aggregation). The entire output for the 398 improver gene signature is listed in Additional file 3.Fig. 2


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 in abatacept improvers. a Blue identifiers designate baseline and black identifiers designate post-treatment samples; b 398 genes showed significant differential expression (p < 0.05) between baseline and post-treatment improver samples during the course of abatacept treatment; c 133 pathways were significantly differentially expressed in improvers (FDR <10 %). Color bar here and on subsequent figures represents single sample Gene Set Enrichment Analysis Normalized Enrichment Score (ssGSEA NES)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Gene and pathway signatures in abatacept improvers. a Blue identifiers designate baseline and black identifiers designate post-treatment samples; b 398 genes showed significant differential expression (p < 0.05) between baseline and post-treatment improver samples during the course of abatacept treatment; c 133 pathways were significantly differentially expressed in improvers (FDR <10 %). Color bar here and on subsequent figures represents single sample Gene Set Enrichment Analysis Normalized Enrichment Score (ssGSEA NES)
Mentions: We identified 398 genes as significantly differentially expressed (p < 0.05, paired t-test) between baseline and post-treatment in the improvers (Fig. 2a). Genes with increased expression in improvers post-treatment included genes associated with general cell growth and cell cycle-related processes such as DNA repair (POLE, SWI5 and RAD52), microtubule cytoskeleton (DOCK7) and mRNA processing (CDK12). Genes with decreased expression in improvers post-treatment included genes associated with immune activation (e.g., T cell proliferation, T cell costimulation, inflammasome) and included chemokine ligands and receptors (CCL7, CCL2 and CXCR6), adhesion molecules (VCAM1, BCAM), T cell co-stimulator molecules (ICOS, ICOSLG), complement components (C3, C1S) and other genes known to play a role in the immune system (Fig. 2b). This subset of the improver gene signature (188 genes) was significantly enriched (FDR <5 %) in several immune system-related terms (e.g., immune system process, immune response, cell activation and leukocyte aggregation). The entire output for the 398 improver gene signature is listed in Additional file 3.Fig. 2

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