Background/Purpose: Targeted therapies have failed to provide sustained disease remission in most patients suffering from immune-mediated inflammatory diseases (IMIDs). Combining existing drugs could overcome this therapeutic ceiling. Deeply characterizing patients who show a very favorable initial response against those patients who do not show any sign of clinical improvement, could provide essential clues on the most potent drug combinations to be used in clinical practice.

Methods: In the framework of the Horizon2020 DoCTIS Consortium (www.doctis.eu), we performed RNA-Seq analyses of the blood transcriptome of a longitudinal cohort of 186 patients of six prevalent immune-mediated inflammatory diseases -rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and systemic lupus erythematosus-, showing extreme clinical responses to therapy. By using a novel systems biology approach capturing the complementarity of each pair of targeted, we show which drug pairs are more likely to be synergistic and in which IMIDs. Analyzing single cell RNA-Seq data (scRNA-Seq) on peripheral blood mononuclear cells of patients we validate the complementarity of the two drugs and provide a mechanism of action.

Results: From a total of 60 drug combinations, our results show that anti-TNF therapy and anti-IL6R receptor therapy (tocilizumab) are highly complementary for the treatment of RA. The complementarity was found to mitigate the non-response signature, lead to a signature closer to that of healthy individuals, was specific of each therapy (non-redundant), and consistent through baseline and follow-up time points. The complementarity of anti-TNF and anti-IL6R was validated using independent patient data. The analysis of longitudinal sc-RNASeq data on PBMCs of patients corroborated the significant combinatorial effect between both drugs, and supported the beneficial effect within a subpopulation of classical monocytes. This cell population was found to be functionally related to inflammatory macrophages in the synovial membrane of RA.

Conclusion: We have identified clinically relevant effective drug combinations in immune-mediated inflammatory diseases through systems biology approaches in patient data. This study provides support for the combination of anti-TNF and anti-IL6R therapy in RA patients to significantly improve efficacy and achieve sustained disease remission.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptome-analysis-of-drug-response-in-a-large-cohort-of-immune-mediated-inflammatory-disease-patients-supports-advanced-combination-therapy-in-rheumatoid-arthritis/