Background/Purpose: For patients with rheumatoid arthritis (RA) who fail to attain remission or low disease activity after 6 months of methotrexate (MTX) treatment, TNF inhibitors should be considered for patients with a high risk of aggressive disease. The objective was to identify genetic variants associated with response to adalimumab (ADA)+MTX in patients with early RA.

Methods: OPTIMA was a 78-week, multicenter, randomized, double-period, double-blind study in which patients were randomized 1:1 to combination therapy with ADA+MTX or MTX alone for the first study period of 26 weeks. Enrolled patients were invited to participate in a genetic sub-study and asked to provide written, informed consent. 384 variants in genes previously shown to be associated with RA or treatment response were assayed using the Illumina BeadXpress GoldenGate Assay. Changes in the 28-joint disease activity score (DAS28) from baseline to 26 weeks and the total Sharp score (TSS) following 26 weeks of treatment were assessed for association with allele status using genotypic tests. 

Results: A total of 413 patients randomized to ADA+MTX were included in the genetic sub-study. Three SNPs within the APOH gene were significantly associated with a response to ADA+MTX (Table). APOH (b2-GPI) has been shown to stimulate macrophages and to produce TNF-a in a TLR4-dependent manner, and some studies have suggested that RA patients display increased levels of autoantibodies against b2-GPI. Additionally, eight SNPs within the MAP2K6 gene, which has been shown to be activated in RA, were significantly associated with a response to ADA+MTX. Other SNPs within genes that have been associated with RA susceptibility or treatment response to TNF-a inhibitors, such as ABCB1, IL21, and STAT4, also showed an association with ADA+MTX treatment. For some genes, such as APOH and MAP2K6, multiple SNPs were identified, suggesting that haplotype analysis could identify stronger associations. In addition, SNPs within TRAF6/RAG1, APOH, and CDK6 were also associated with a change in TSS (DTSS ≥0.5).

Table. SNPs Significantly Associated with Treatment Response to ADA+MTX
Gene	SNP	Additive AA vs Ab vs bb (p-value)	Additive AA vs Ab vs bb False Discovery Rate (q-value)	Dominant Major AA vs Ab + bb (p-value)	Dominant Major AA vs Ab + bb False Discovery Rate (q-value)	Dominant Minor AA + Ab vs bb (p-value)	Dominant Minor AA + Ab vs bb False Discovery Rate (q-value)
ABCB1	rs3789244	NS	NS	0.040	0.58	NS	NS
ABCB1	rs7787082	NS	NS	0.046	0.61	NS	NS
APOH	rs4581	< 0.001	0.14	< 0.001	0.03	NS	NS
APOH	rs8178835	< 0.001	0.14	< 0.001	0.03	NS	NS
APOH	rs7212060	0.007	0.24	0.002	0.14	NS	NS
MAP2K6	rs11656130	NS	NS	NS	NS	0.022	0.55
MAP2K6	rs817543	0.006	0.23	0.003	0.14	0.031	0.55
MAP2K6	rs817546	NS	NS	NS	NS	0.031	0.55
MAP2K6	rs2716225	NS	NS	NS	NS	0.037	0.55
MAP2K6	rs707247	0.010	0.30	0.003	0.14	NS	NS
MAP2K6	rs11869348	0.015	0.42	0.004	0.17	NS	NS
MAP2K6	rs817565	0.032	0.51	0.015	0.39	NS	NS
MAP2K6	rs2716191	0.041	0.51	0.015	0.39	NS	NS
STAT4	rs7572482	NS	NS	0.026	0.52	NS	NS
STAT4	rs12327969	0.023	0.49	NS	NS	NS	NS
NS, not significant.

Conclusion: Genetic polymorphisms in genes such as ABCB1, APOH, MAP2K6, and STAT4 were shown to associate with ADA+MTX response in the OPTIMA study. These results may prove useful for the development of future diagnostic tests or personalized therapeutics for combination therapy treatment with ADA+MTX.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-genetic-variants-associated-with-response-to-adalimumab-plus-methotrexate-in-patients-with-early-rheumatoid-arthritis/