medwireNews: UK researchers have identified a pretreatment transcriptome signature that may be associated with a DAS28 response to adalimumab in people with rheumatoid arthritis (RA).
Darren Plant, from the University of Manchester, and colleagues used a human transcriptome array to measure the transcriptome in blood samples from 50 good responders to adalimumab and 20 non-responders who were all participating in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate.
A good response was defined as a DAS28 score of less than 2.6 points at 3 months with an improvement of more than 1.2 points from baseline, while non-response was classed as a DAS28 improvement of less than 0.6 points with a 3-month DAS28 score above 5.1 points.
Plant and team report in Arthritis Research & Therapy that there was no significant difference in transcriptome expression between good responders and non-responders either before or after 3 months of treatment with adalimumab.
There were also no transcriptome differences from baseline to 3 months among the non-responders.
However, the researchers identified 813 transcripts, corresponding to 491 unique genes, that were differentially expressed to a significant degree between the two timepoints in good responders. Of these, 202 transcripts were more abundant and 611 were less abundant at 3 months relative to baseline.
The greatest degree of enriched expression was observed in pathways for altered T- and B cell signaling in RA, the researchers note. The upstream regulators with the greatest difference in expression included TGM2, CEBPA, CSF2, TNF, and IRF4.
To validate their findings, Plant et al measured the expression of 104 transcripts in 11 good- and 11 non-responders. These transcripts were selected based on magnitude of effect or prior association with RA or the immune system.
They found that, in the good responders, 17 transcripts were significantly differentially expressed in the same direction of change as the initial discovery cohort. By contrast, there was no evidence of significant differential expression for any of the transcripts among the non-responders.
The investigators say that future studies should “test the differentially expressed transcripts identified herein against different drugs in order to elucidate whether they are general markers of response or specific to this class of drug.”
They add: “The inability to identify baseline markers [of response versus no response] suggests that further discovery studies should redirect efforts to other data types or include on-treatment sampling as part of the study design.”
However, the authors also suggest that “the high levels of disease activity seen at pre-treatment in all study participants may be obscuring detection of pretreatment gene expression signatures that are relevant to future treatment response.”
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Arthritis Res Ther 2021; 23: 80