The evolution in our understanding of the genetics of rheumatoid arthritis and the impact on novel drug discovery

ABSTRACT

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by chronic inflammation of the joints and affects 1% of the population. Polymorphisms of genes that encode proteins that primarily participate in inflammation may influence RA occurrence or become useful biomarkers for certain types of anti-rheumatic treatment.

Areas covered: The authors summarize the recent progress in our understanding of the genetics of RA. In the last few years, multiple variants of genes that are associated with RA risk have been identified. The development of new technologies and the detection of new potential therapeutic targets that contribute to novel drug discovery are also described.

Expert opinion: There is still the need to search for new genes which may be a potential target for RA therapy. The challenge is to develop appropriate strategies for achieving insight into the molecular pathways involved in RA pathogenesis. Understanding the genetics, immunogenetics, epigenetics and immunology of RA could help to identify new targets for RA therapy. The development of new technologies has enabled the detection of a number of new genes, particularly genes associated with proinflammatory cytokines and chemokines, B- and T-cell activation pathways, signal transducers and transcriptional activators, which might be potential therapeutic targets in RA.

KEYWORDS:

• Rheumatoid arthritis
• genes
• therapy

Article Highlights

• The pathogenesis of RA is complex and not fully understood. Therefore, we are unable to design effective medicines to cure RA.

• Researchers have identified multiple loci, both in and outside of the HLA locus, that are associated with an elevated RA risk.

• Genetic polymorphisms influence the treatment outcomes and toxicities of MTX, leflunomide and sulfasalazine in RA patients.

• Some SNPs of the TNF gene may influence anti-TNF therapy.

• Polymorphisms of the TNFRII, IL-6 and PTPRC genes are likely to become markers of anti-TNF treatment efficacy.

• The response to tocilizumab could be affected by variations in the IL-6 receptor gene.

• SNPs of the Fcγ receptor type IIIA, IL-6, TGFβ1, BAFF and type 1 interferon pathway genes could become useful biomarkers of anti-CD20 treatment efficacy.

• The development of new technologies and the detection of new potential therapeutic targets contribute to novel drug discovery.

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

This manuscript was not funded.