Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
A previous hypothesis-seeking study examining baseline phenotypic expression of mRNA in a Phase 2 clinical trial of tabalumab (also known as LA294 or LY2127399) suggested that expression of the gene CLEC4C might serve to help stratify patients for their clinical response to tabalumab. CLEC4C-expressing cells appear to mediate their immunoregulatory effects through direct cell-cell contact or indirectly through the production of cytokines including TGF-beta and IL-10 and appear to influence T regulatory cells via these mechanisms. We hypothesize that this immunoregulatory cell may have a role in pathogenesis of RA and may influence drug treatment response. The primary aim of our study was to characterise the phenotypic expression of the gene CLEC4C, as measured in peripheral blood among a well characterised cohort of rheumatoid arthritis patients receiving different therapies.
Methods:
Total RNA was extracted from whole blood and converted to cDNA. A total of 322 samples were available for analysis, consisting of four groups: 1) 93 healthy controls 2) 72 RA patients with recent onset disease receiving methotrexate 3) 85 RA patients who have failed methotrexate and are receiving a TNFi 4) 72 RA patients who had failed at least one TNFi due to lack of efficacy and were receiving another biologic. Quantitative real time PCR was carried out to measure the expression of CLEC4C and three reference genes. CLEC4C expression was normalised and quantified using the delta CT method. Linear regression was used to correlate expression with treatment group.
Results:
A significant difference in CLEC4C expression was observed between sample groups (p=2.5×10-5). CLEC4C expression was significantly higher in healthy individuals compared to all RA patients (p=8.9×10-6). All patient groups showed lower expression when compared to healthy controls and this difference is greatest in patients treated with biologic therapies including TNFi (Table 1).
|
Table 1: Linear regression results comparing CLEC4C expression in patients and healthy controls |
|||||
|
Group |
Coefficient |
Standard error |
P value |
95% confidence interval |
|
|
Controls |
Reference |
– |
– |
– |
– |
|
MTX |
-0.0018 |
0.0006 |
0.007 |
-0.0032 |
-0.0005 |
|
TNFi |
-0.0027 |
0.0007 |
9.89×10-5 |
-0.0040 |
-0.0013 |
|
Other Biologic |
-0.0027 |
0.0007 |
0.00036 |
-0.0042 |
-0.0012 |
Conclusion:
Differences in expression of CLEC4C were found between RA patients and age- and sex-matched healthy controls with statistically significant higher levels of expression of CLEC4C seen in healthy controls. Among RA patients the highest levels of CLEC4C were seen in the RA patients who had been treated only with methotrexate and were biological naive; lowest levels of CLEC4C in those treated with one or more biologic agent including TNFi. These results suggest that stratification for CLEC4C expression may be valuable to assure balance between patient subgroups in clinical trials in that difference in baseline CLEC4C expression could be a source of unanticipated bias influencing trial outcome. Finally, determining the biologic basis for these observed differences in CLEC4C gene expression among different subgroups of patients, based upon prior treatment, may help advance our understanding of disease pathogenesis in RA.
Disclosure:
A. Yarwood,
Eli Lilly and Company,
2;
J. Cobb,
Eli Lilly and Company,
2;
K. McAllister,
Eli Lilly and Company,
2;
J. Barnes,
Eli Lilly and Company,
2;
E. R. Dow,
Eli Lilly and Company,
9;
M. A. Penny,
Eli Lilly and Company,
9;
R. W. Hoffman,
Eli Lilly and Company,
9;
A. Barton,
Eli Lilly and Company,
2.
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