Using pharmacogenetics to predict methotrexate response in rheumatoid arthritis patients

ABSTRACT

Introduction

Methotrexate (MTX) is a folate antagonist and a first-line drug for the treatment of rheumatoid arthritis (RA). However, in up to 30% of cases, MTX monotherapy is insufficient, while a further 30% of patients suffer with severe adverse effects. Despite extensive clinical evidence, it is not currently possible to predict therapy outcomes and drug toxicity for MTX. Therefore, to establish biomarkers of toxicity and successful disease remission, pharmacogenomic approaches are rapidly becoming more popular.

Areas

This review summarizes recent pharmacogenomic studies evaluating MTX efficacy and toxicity. In recent years, multiple genetic alterations associated with MTX therapy outcomes and toxicity have been identified in genes associated with MTX metabolism and effector pathways. However, the data are inconsistent and require further validation.

Expert opinion

To date, several single nucleotide polymorphisms (SNPs) have been linked with MTX efficacy. However, thanks to equivocal data, pharmacogenomic testing in routine clinical practice remains a distant prospect. Genome-wide association studies (GWAS) could facilitate the evaluation of current SNPs, and support searches for new genetic variations Once achieved, only then will it be possible to introduce more personalized and individualized therapies for RA patients.

KEYWORDS:

• Rheumatoid arthritis
• genome-wide association studies
• pharmacogenomics
• methotrexate

Article highlights

• Association studies have revealed over 120 loci in 25 genes that potentially influence MTX response and toxicity. But results are inconclusive.

• The largest meta-analysis underlines the potential clinical significance of the following SNPs: RFC1 80G>A, MTHFR C677T, A1298C, 677TT, and 1298CC, ABCB1 C3435T, ATIC 347C/G.

• In collecting high-quality data, GWAS have identified loci for further prospective research, with the ultimate goal of improving and personalizing medical algorithms.

• Intergenic rs6593803 and NRG3 rs168201, identified by GWAS provide potential associations with MTX responses, treatment outcomes, and/or side effects.

• Further pharmacogenomics studies are crucial to establish reliable biomarkers for MTX responses and toxicity, and to introduce more personalised RA therapies.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The project was financed by the Minister of Science and Higher Education in the ‘Regional initiative of excellence’ program, in years 2019-2022, [No. 002/RID/2018/19].