Background/Purpose: A broad range (6-55%) of patients classified as having undifferentiated arthritis (UA) tend to progress to rheumatoid arthritis (RA), suggesting that UA in these patients may represent the early stages of RA. Our goal was to identify transcriptional biomarkers predictive of progression from UA to RA so that these patients can be differentiated from other UA patients and targeted for early aggressive treatment. We also examined biological changes that accompanied disease progression from UA to RA and spontaneous remission.

Methods: Patients (n=54) with inflammatory arthritis of one or more joints for >4 weeks, but < 12 months, were enrolled in the Vilnius University Hospital Santaros Klinikos Rheumatology Centre early UA cohort and followed prospectively for 12 months. Blood samples were collected at study entry (T0, n=52) and at 12 months (T1, n=35). We examined the transcriptomes at each timepoint using bulk RNA-sequencing. We performed Differential Expression Analysis (a) between UA groups (pre-RA vs pre-remission) at the T0 baseline to identify biomarkers predictive of progression to RA, and (b) within groups (paired samples: T1 vs T0) to assess transcriptional changes associated with progression to RA or spontaneous remission. Genes were considered differentially expressed (DE) using FDR < 0.05 and fold-change >=2. Functional enrichment analysis was also performed.

Results: Of the 54 UA patients, 33 progressed to RA by 12 months, while 21 went into remission. At the T0 baseline, 43 genes were DE between the two UA (pre-RA and pre-remission) groups. These included several genes previously implicated in RA that were over-expressed in the pre-RA group at T0 (e.g. MAOA, DAAM2 and IFI27) and some that were under-expressed (e.g. SOX5, IGLV3-1 and S100B). Functional enrichment analysis identified myeloid cell homeostatis and differentiation pathways significantly enriched among the DE genes. Analysis of samples available at T1 from UA patients who progressed to RA (n=25) or went into remission (n=10), revealed 229 DE genes between the RA and remission groups. These included genes previously associated with RA such as CD177, S100A12, and MMP9 being over-expressed in the RA group, consistent with previous studies, and many immunoglobulin genes being under-expressed. Inflammatory and immune response pathways were significantly enriched among the DE genes. Surprisingly, as UA progressed to RA over time, no significant DE genes were detected between T0 and T1. In contrast, as UA went into remission, 13 genes were DE between T0 and T1, including some genes previously implicated in RA (e.g. CASP5 and OLFM4) which significantly decreased in expression from T0 to T1.

Conclusion: In our cohort, at the pre-RA stage, UA patients exhibited gene expression signatures that may represent predictive biomarkers of progression to RA. The absence of longitudinal transcriptomic changes when UA progressed to RA suggest that molecular mechanisms that drive the disease process in RA were perhaps already under way at the UA (pre-RA) stage, at our study baseline. Remission, on the other hand, was accompanied by decreasing expression of some genes known to have a pro-inflammatory role in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptomic-biomarkers-of-progression-from-undifferentiated-arthritis-to-rheumatoid-arthritis/