Rheumatoid Arthritis: Different Mechanisms for Different Joints

Although new approaches to the treatment of rheumatoid arthritis (RA) are being investigated, including targeting of B-cell-mediated immunity or pro-inflammatory cytokines,¹ the heterogeneity of RA pathologic processes renders development of adapted treatments challenging. In addition, overall disease burden (i.e. RA remission) vs individual joint synovitis is used to assess drug effectiveness in clinical trials.² Although RA initially affects small joints of the hand before spreading to other joints, there is poor understanding of differential joint involvement.

In a research article recently published in Nature Communications, investigators hypothesized that fibroblast-like synoviocytes (FLS) which line joints had variable epigenetic patterns, underlying variations in joint inflammation and response to treatment.³ Epigenetic mechanisms, defined as heritable changes in gene expression independent of changes in DNA sequence, have been implicated in the pathogenesis of autoimmune disorders. In particular, DNA methylation and microRNAs have been involved in RA.⁴

A previous study had identified distinct DNA methylation patterns in FLS from RA and osteoarthritis (OA) patients.⁵ DNA methylation levels of cultured FLS from 19 RA and 5 OA patients were examined through genome-wide analysis. Authors found 29,956 differentially methylated loci (DMLs) between RA and OA cells; 71.5% of the 450 corresponding differentially methylated genes (DMGs) overlapped (Hypergeometric test; P value=4.26e-284). These DMGs were related to pathways involved in inflammation, immunity and/or matrix destruction, strengthening the involvement of epigenetic mechanisms in RA.

In a larger sample (30 RA and 16 OA), 13,577 DMLs in 1,714 DMGs were identified; 67 significantly enriched pathways (including 44 from previous data) involved in inflammation and immune responses were also identified.

When comparing knee and hip joints in RA patients (12 knees and 10 hips), authors found 2,232 hypermethylated and 1,507 hypomethylated DMLs in RA knee FLS compared to hip, corresponding to 500 DMGs (285 hypermethylated, 210 hypomethylated, 5 mixed) in knee FLS. In addition, 11 unique differentially methylated biological pathways between RA hips and knees were identified, including the JAK-STAT pathway activated by Interleukin-6 (IL-6), indicating a distinct involvement of this cytokine in hip and knee OA mechanisms (Hypergeometric test; P value<.05). IL-6 expression was also found to be 10.8 fold higher in RA hips vs knee synovia (P =.042; n=13 RA hip, 22 RA knee).

RNA sequencing was performed to determine whether differences observed between hip and knee FLS had a functional impact. 107 differentially expressed genes (DEGs) were identified (with gene expression fold change >2, P<.05); differentially expressed pathways included the IL-6 pathway. Of the drugs currently approved to treat RA, in clinical trials, or discontinued, authors found 6 targeting the JAK-STAT pathway.

The present study identifies RA- and joint-specific epigenetic mechanisms, including DNA methylation, as well as joint-specific genes, and signaling pathways, suggesting that therapeutic intervention should be adapted to the affected joint(s).

References

1.Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology (Oxford). 2014;53(9):1560-9.

2.Kuriya B, Arkema EV, Bykerk VP, Keystone EC. Efficacy of initial methotrexate monotherapy versus combination therapy with a biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission. Ann Rheum Dis. 2010;69(7):1298-304.

3.Ai R, Hammaker D, Boyle DL, et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat Commun. 2016;7:11849.

4.Richardson BC, Patel DR. Epigenetics in 2013. DNA methylation and miRNA: key roles in systemic autoimmunity. Nat Rev Rheumatol. 2014;10(2):72-4.

5. Whitaker, J. W. et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 5, 40 (2013).