Background/Purpose:

Despite the success of anti-TNF therapies in RA, ~ 30 % of patients are non-responders. Several studies have focused on understanding the biology underlying non-response in these patients, and this remains an area of active investigation. We conducted a comprehensive molecular profiling of biologic naïve RA patients being treated with anti-TNF therapy in combination with MTX, prior to initiating (baseline) and following 3 months of treatment. The aim of the study was to understand the molecular mechanisms (other than drug neutralization), that affect clinical response to anti-TNF and to identify potential predictive markers that could allow us to differentiate responders and non-responders at baseline.

Methods:

Two independent cohorts of 52 and 41 RA patients were selected from the Corrona CERTAIN registry. Clinical response at three months was defined according to EULAR criteria. Patients were included in each cohort only if a minimum level of anti-TNF was detected in the 3 month plasma sample to assure drug exposure.

Whole-blood RNA (PAXgene) and plasma samples from baseline and after 3 months of treatment were profiled using a broad array of technologies including RNAseq (Illumina HiSeq2500), shotgun and targeted proteomics, and glycan / glycopeptide analysis. A cell-specific transcriptional data analysis methodology was developed and applied to results of RNAseq analysis to enable characterization of the most common immune cell sub-populations.

Results:

Results from each cohort show a strong treatment-related molecular signature between 3 months and baseline, and also a high level of correlation (ρ=0.7; permutation p<10^-3), between cohorts. Interestingly, no significant difference could be established between responders and non-responders in terms of treatment signature. Cell-specific transcriptional profiling analysis indicated a decrease in neutrophil markers at 3 months (permutation p<0.01), which is concordant with observed changes in neutrophil counts. Shotgun proteomics in plasma showed a significant reduction of acute phase proteins, including CRP. Results at baseline, comparing responders to non-responders, demonstrated a lower concordance across the two cohorts, however, cell-specific analysis indicated increased representation of innate cell type signatures in responders and, conversely, increased expression of adaptive cell type signatures in non-responders. These results were not only conserved between the two cohorts, but were also observed when this analysis was applied to other independent publicly available RA datasets assessing response to anti-TNF treatment.

Conclusion:

Results from this comprehensive molecular profiling study identified that differences in innate / adaptive immune cell signatures at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy. These observations were supported by analysis of independent, publicly available RA datasets, and could potentially lead to an approach to patient selection, resulting in improved treatment outcomes.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-profiling-of-ra-patients-suggests-a-differential-involvement-of-adaptive-and-innate-cell-populations-in-response-to-anti-tnf-treatment/