Kimberly Coffman

Introduction: Rheumatoid Arthritis (RA) is an autoimmune disease which results in chronic inflammation and progressive damage of synovium of joints.¹ RA affects approximately 0.5-1% of the general population and is distributed relatively consistently geographically.1-2 Damage is caused by an expansion of the lining of the synovium which leads to an increase in proteases and pro-inflammatory cytokines including Tumor Necrosis Factor (TNF), IL-6 and IL-1, and through infiltration of immune cells which produce autoantibodies, leading to damage of the synovium lining, cartilage and bone.¹ 40% of RA patients never respond adequately to treatment, which means incredibly high cost of treatment and significant side effects without gain for the patient.^1-2 A significant area of current research in RA is precision treatment based on prescreening for genetic/epigenetic predispositions and biomarkers that may indicate a more robust response to one treatment over another.^2-3  Methods: Genome wide association Studies (GWAS) performed to identify differential methylation loci (DMLs), positions in which methylation levels that may differ between responders and nonresponders.^2,4,5 One study used peripheral blood and another used synovial fluid biopsy.^2,4,5 Two disease modifying antirheumatic drugs (DMARDs), Methotrexate and Etanercept, were analyzed.^2,5  Results: One study found that methylation differed significantly between responders and nonresponders to Etanercept, a TNF inhibitor, at 5 different sites.⁵ The most significant of these sites was the LRPAP1 locus, which is highly expressed in mononuclear cells.⁵ Inflammatory arthritis associated genes such as P13 and MMP-5 that were only expressed in the purified macrophage sample from synovial fluid, but that was not present in peripheral blood, have been identified.⁵ Hypermethylation of CpG-2 and hypomethylation of CpG-3 showed the greatest promise for clinical testing and yielded a sensitivity of 80% and a specificity of 90.9% in predicting response to Methotrexate.²  Conclusions: Analysis of methylation levels at LRPAP1, CpG-2 and CpG-3 could provide predictions of response to DMARDs for RA patients.^2,5 Both peripheral blood and synovial fluid biopsy can be collected in a brief outpatient visit.^2,5 However, P13 and MMP-5 are only found to be turned off only in the synovial fluid, indicating that biopsies may provide a more accurate picture of drug response.⁵ This could limit waste on inadequate treatment and avoid unnecessary side effects with no potential benefits.

1. Smolen, J., Aletaha, D., Barton, A., Burmester, G., Emery, P., Firestein, G., Yamamoto, K. (2018). Rheumatoid arthritis. – Macmillan Publishers Limited.
2. Mandelin, A.; Homan, P.; Shaffer, A.; Cuda, C.; Dominguez, S.; Bacalao, E.; Carns, M. ; Hinchcliff, M. ; Lee, J. ; Aren, K. ; Thakrar, A. ; Montgomery, A.; Louis Bridges, S.; Bathon, J.; Atkinson, J.; Fox, D.; Matteson, E.; Buckley, C.; Pitzalis, C.; Parks, D.; Hughes, L.; Geraldino‐Pardilla, L.; Ike, R.; Phillips, K.; Wright, K.; Filer, A.; Kelly, S.; Ruderman, E.; Morgan, V.; Abdala‐Valencia, H.; Misharin, A.; Budinger, G.; Bartom E.; Pope, R.; Perlman H. and Winter D. (2018). Transcriptional profiling of synovial macrophages using minimally invasive Ultrasound‐Guided synovial biopsies in rheumatoid arthritis. Arthritis Rheumatol., Epub ahead of print
3. Favalli, E. G., Raimondo, M. G., Becciolini, A., Crotti, C., Biggioggero, M., & Caporali, R. (2017). The management of first-line biologic therapy failures in rheumatoid arthritis: Current practice and future perspectives https://doi.org.ezproxy.library.tamu.edu/10.1016/j.autrev.2017.10.002
4. Glossop J.; Nixon N.; Emes R., Sim J.; Packham J.; Mattey D.; Farrell W.; Fryer A. (Epigenomics). Dna methylation at diagnosis is associated with response to disease-modifying drugs in earlyrheumatoid arthritis. 2017, 9(4), 419-428.
5. Plant D, Webster A, Nair N, et al. (2016). Differential methylation as a biomarker of response to etanercept in patients with rheumatoid arthritis. Arthritis & Rheumatology, 26(6), 1353-1360.