Background Early recognition of development of rheumatoid arthritis (RA) allows timely start of treatment. It is known that antibodies against citrullinated proteins (ACPA) and rheumatoid factor (RF) have a predictive value for development of RA within 5 years. Since only 20-40% of ACPA+ and/or RF+ seropositive arthralgia patients develop arthritis, better prognostic markers are required. Recently, we reported gene signatures in the peripheral blood (PB), involving interferon (IFN) response gene activity and B-cell related genes, which are associated with the development of arthritis.
Objectives The objective of this study is to validate the signatures of IFN response gene activity and B-cell related genes in independent cohorts.
Methods PB samples of an independent group of 40 seropositive arthralgia patients from the Amsterdam Reade cohort who are clinically followed for arthritis development were analyzed for their IFN-response gene activity, defined as a score based on the average expression of 7 IFN-response genes. In addition PB mononuclear cells (MCs) of 22 pre-onset RA, 25 RA patients and 48 population based controls (PC) from the Medical Biobank of Northern Sweden (Umeå) were studied. FACS-analysis for B-cell markers expression was performed on PB from 87 seropositive arthralgia patients and 30 healthy controls (HC) from the Amsterdam Reade cohort. qPCR for B-cell markers expression was performed in 45 seropositive arthralgia patients and 6 HC from the Amsterdam Reade cohort.
Results Of the 40 seropositive arthralgia patients analyzed for INF-scores, 19 developed arthritis within a median period of 11 months (IQR 9-28). Comparative analysis of INF-score high and low patients confirmed that an increased IFN-score is associated with conversion to arthritis (p=0.025). In addition, the IFN-score was measured in PBMC from RA, pre-onset RA patients and PC from the Medical Biobank of Northern Sweden. Comparative analyses between the groups revealed that both pre-onset RA patients as well as RA patients had significantly increased IFN-scores compared to HC (Mann-Whitney U test p=0.006 and p=0.008, respectively).
Of the 87 seropositive arthralgia patients analyzed for B-cell marker expression, 22 developed arthritis within a median period to conversion of 11 months (IQR 5-13). Low B-cell markers expression was significantly associated with conversion to arthritis (p=0.01). An interim analysis with qPCR showed a strong trend towards decreased B-cell transcript markers and arthritis conversion (p=0.07).
Conclusions These results provide evidence for the validation for a role of IFN-activity and low B-cell presence in the preclinical phase of RA. Further studies are aimed to demonstrate the diagnostic value of these markers.
Acknowledgements This research was supported by the Center for Translational Molecular Medicine (CTMM) consortium “TRACER”.
Disclosure of Interest None Declared
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