Background/Purpose: Available clinical tools do not adequately identify treatment non-responders in early rheumatoid arthritis (RA) leading to delayed disease control. Tools informed by molecular phenotype may aid treatment decisions. Using an aptamer based assay that measures the relative quantity of 1310 proteins, (SOMAscan), we sought to identify predictors of Methotrexate (MTX) response in Disease Modifying Anti-rheumatic Drug (DMARD) naive patients with less than 1 year of RA (ERA).

Methods: Sera from 36 DMARD naïve seropositive ERA (female 67%, rheumatoid factor (RF) positive 47%, baseline symptom duration 4 (1.9) months, baseline DAS28CRP 5.1 (SD 1.2) were assayed for SOMAmer protein expression. All patients met ACR/EULAR 2010 criteria for RA and all received MTX monotherapy. At one year, clinical response was defined by change in DAS28CRP (dDAS) and radiographic outcome by the presence of erosions on hand and feet radiographs and Sharp score. Pre-treatment protein expression levels were log2 transformed and correlated with their corresponding log2transformed dDAS using a Pearson’s R-squared (RSQ) applied across the cohort. A constant offset was included to account for negative dDAS values. The proteins with RSQ over a threshold had their expression values weighted into a linear combination SCORE. The value of the threshold was manually, iteratively tuned to yield an optimal correlation of SCORE against dDAS using the smallest number of proteins. Biological processes of included proteins were identified using an in-house enrichment tool. The SCORE was included in logistical regression models to predict radiographic outcome.

Results: The mean dDAS at one year was -1.9(SD1.6), 47% achieved remission (DAS<2.6) and 19(53%) had erosions at one year (median Sharp score 3 (range 0-18). A panel of 9 proteins each with RSQ>0.18 correlated with dDAS (overall RSQ 0.58). Three proteins enriched to processes regulating cell proliferation (BIRC7, MMP7, CXCL9). SCORE did not correlate with one year radiographic Sharp scores and were similar between patients with or without erosions. In multivariable models including RF, age and sex, SCORE predicted remission (OR 0.01; 95% confidence interval 0.001-0.2) but did not predict the presence of erosions at one year. The dynamic range of protein expression values suggests this assay could be transferable to more clinically accessible protein quantification technologies.

Conclusion: High content proteomic approaches based on aptamers can assist the development of biologically based prediction tools. While further validation in cohorts with expanded disease activity and broader treatment is needed, this pilot study suggests a panel of proteins reflecting cellular proliferation predicts treatment response to MTX monotherapy in ERA however, different biomarkers are needed to predict erosions.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-response-in-early-rheumatoid-arthritis-predicted-using-a-somamer-proteomic-assay/