Abstract
BackgroundEstablished rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls. It is unclear, however, if in the pre-arthritis phase of clinically suspect arthralgia (CSA) expression of immune genes differ between patients who do or do not develop clinically evident inflammatory arthritis (IA).MethodsTwo hundred thirty-six consecutive patients presenting with arthralgia clinically suspected for progression to RA were followed until IA development or else for median 24 months (IQR 12–26). Baseline whole blood RNA expression was determined for a previously identified set of 133 genes associated with the innate and adaptive immune system by dual-color reverse-transcription multiplex ligation-dependent probe amplification (dcRT-MLPA) profiling. Cox proportional hazard models were used.ResultsTwenty percent of CSA patients developed IA. After correction for multiple testing, expression levels of six genes (IFNG, PHEX, IGF-1, IL-7R, CD19, CCR7) at the time of presentation were associated with progression to IA. PHEX and IGF-1 were highly correlated with each other (ρ = 0.97). In multivariable analysis correcting for the different genes, expressions of IL-7R and IGF-1 were independently associated with IA development (p = 0.025, p = 0.046, respectively). Moreover, IL-7R and IGF-1 remained significantly associated even after correction for known predictors (ACPA, CRP, imaging-detected subclinical joint inflammation; p = 0.039, p = 0.005, respectively). These genes are also associated with RA development.ConclusionsIL-7R and IGF-1 were differentially expressed between CSA patients who did or did not progress to IA, independent from regularly used predictors. These biomarkers may become helpful in prognostication of CSA patients. Furthermore, because both genes are associated with T cell functioning, T cell dysregulation may mediate progression from arthralgia to arthritis.
Highlights
Established rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls
After correction for multiple testing and adjusting for age, gender, and assay plate, six genes were significantly associated with inflammatory arthritis (IA) development, namely Interferon gamma (IFNG), phosphate regulating endopeptidase homolog X-linked (PHEX), insulin growth factor-1 (IGF-1), IL-7R, cluster of differentiation-19 (CD19), and C-C chemokine receptor type 7 (CCR7)
IFNG was only weakly expressed in whole blood, and to confirm dcRT-MLPA data, expression was measured by Quantitative polymerase chain reactions (qPCRs) (Additional Figure 2A-B)
Summary
Established rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls. It is unclear, if in the pre-arthritis phase of clinically suspect arthralgia (CSA) expression of immune genes differ between patients who do or do not develop clinically evident inflammatory arthritis (IA). During development of RA, the occurrence of clinical arthritis is preceded by a phase where patients have symptoms, which are recognized by rheumatologists as arthralgia suspicious for progression to RA (clinically suspect arthralgia, CSA). The pathophysiology of RA development is still incompletely understood, and it is unclear which processes are related to the final hits that mediate progression from arthralgia to clinical arthritis and RA
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