Genetic variations predict response to MTX, etanercept in early RA

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Genetic variations predict response to MTX, etanercept in early RA

Sept 22, 2004 Janis

Birmingham, AL - Specific genetic variations in the HLA-DRB1 and LTA-TNF

regions are associated with response to treatment of early rheumatoid

arthritis (RA) and might be useful for selecting patients who areor are

notlikely to benefit from methotrexate or etanercept, according to

researchers [1]. The study is reported in the September 2004 issue of

Arthritis & Rheumatism.

" We demonstrated that genetic variation in 2 regions is associated with

response to treatment of early RA. The 2 regions (HLA DRB1 and LTA-TNF) are

very close to one another, and both are in the 4.1 kilobase major

histocompatibility complex (MHC) region, " senior author Dr S Louis Bridges

Jr (University of Alabama, Birmingham) tells rheumawire.

Genotyping correlated with etanercept, MTX response

The investigators genotyped 457 patients with RA duration of <3 years who

were participating in a trial comparing weekly methotrexate (MTX) vs 2

dosages of etanercept (low-dose 10 mg twice weekly and standard-dose 25 mg

twice weekly). The primary outcome measure was 50% improvement in disease

activity after 12 months of treatment, judged according to American College

of Rheumatology criteria.

The genotyping was undertaken to explore 2 areas. The first was a previously

identified association between HLA-DRB1 alleles containing the shared

epitope (SE) at beta-chain positions 70-74, disease severity, and response

to treatment. The second was the possibility that RA severity might be

influenced by genetic variation in the lymphotoxin alpha-tumor necrosis

factor (LTA-TNF).

With the introduction of new therapies for RA . . . the identification

of genetic and other predictors of treatment response would provide valuable

information for therapeutic decisions, due to wide variation in costs,

outcomes, and responses to specific agents.

The researchers write, " With the introduction of new therapies for RA,

particularly TNF antagonists, the identification of genetic and other

predictors of treatment response would provide valuable information for

therapeutic decisions, due to wide variation in costs, outcomes, and

responses to specific agents. Genetic predictors are particularly attractive

because they can be determined at the time of RA diagnosis. "

Two copies of shared epitope help determine response

Subjects were genotyped for HLA-DRB1 alleles and for polymorphisms in TNF,

LTA, and 5 other genes. The researchers examined the association of each

candidate polymorphism with the achievement of an ACR50 response.

Only HLA-DRB1 alleles were significantly associated with response to

treatment. Patients who had 2 copies of the SE also had the best responses

to standard-dose etanercept and were more likely to respond to standard-dose

etanercept than to MTX (76% vs 48%, OR 3.5). The number of SE copies did not

affect response to low-dose etanercept or MTX.

The 2 haplotypes associated with " exceptionally good responses to treatment "

involved HLA-DRB1alleles *0404 and *0101, both of which encode the SE. The

investigators concluded that, at least for RA patients with early active

disease, genetic variation in the HLA region influences response to

treatment. " In view of the costs associated with etanercept treatment, our

results have important clinical implications, because they provide a

potential mechanism for identifying patients who are more likely to benefit

from this treatment, " they write.

Clinical test not likely anytime soon

Several barriers must be surmounted before this approach has clinical

utility, however. Bridges emphasizes that HLA genotyping is commercially

available but not clinically indicated. TNF and LTA genotyping are available

only for research purposes.

" The genotyping of the HLA DRB1 is complex and relatively expensive (about

$200 in commercial labs). The TNF and LTA genotyping is somewhat more

straightforward and cheaper. However, the cost is a moot point with regard

to clinical practice, as neither genotyping is clinically indicated at

present, and further work needs to be done (ie, corroboration in larger

studies), " Bridges tells rheumawire.

" This work raised the question of why these genetic variants were associated

with treatment response. Perhaps it is due to genetic variants in 1 of the

approximately 120 other genes in this region, " Bridges adds.

The researchers ruled out the possibility that patients with the HLA-DRB1

alleles encoding the shared epitope responded better because they had more

severe disease. " There is a well-known correlation between those alleles and

more severe disease in whites. However, this was not the case in our study,

as the baseline severity was similar in those subjects with and without

HLA-DRB1 alleles encoding the shared epitope, " Bridges says.

Source

1. Criswell LA, Lum RF, KN, et al. The influence of genetic

variation in the HLA-DRB1 and LTN-TNF regions on the response to treatment

of early rheumatoid arthritis with methotrexate or etanercept. Arthritis

Rheum 2004; 50:2750-2756.