Association between type I interferon pathway activation and clinical outcomes in rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider

Abstract

BackgroundType I interferons (IFN-I) contribute to a broad range of rheumatic and musculoskeletal diseases (RMDs). Compelling evidence suggests that the measurement of IFN-I pathway activation may have clinical value. Although several IFN-I pathway assays have been proposed, the exact clinical applications are unclear. We summarise the evidence on the potential clinical utility of assays measuring IFN-I pathway activation.MethodsA systematic literature review was conducted across three databases to evaluate the use of IFN-I assays in diagnosis and monitor disease activity, prognosis, response to treatment and responsiveness to change in several RMDs.ResultsOf 366 screened, 276 studies were selected that reported the use of assays reflecting IFN-I pathway activation for disease diagnosis (n=188), assessment of disease activity (n=122), prognosis (n=20), response to treatment (n=23) and assay responsiveness (n=59). Immunoassays, quantitative PCR (qPCR) and microarrays were reported most frequently, while systemic lupus erythematosus (SLE), rheumatoid arthritis, myositis, systemic sclerosis and primary Sjögren’s syndrome were the most studied RMDs. The literature demonstrated significant heterogeneity in techniques, analytical conditions, risk of bias and application in diseases. Inadequate study designs and technical heterogeneity were the main limitations. IFN-I pathway activation was associated with disease activity and flare occurrence in SLE, but their incremental value was uncertain. IFN-I pathway activation may predict response to IFN-I targeting therapies and may predict response to different treatments.ConclusionsEvidence indicates potential clinical value of assays measuring IFN-I pathway activation in several RMDs, but assay harmonisation and clinical validation are urged. This review informs the EULAR points to consider for the measurement and reporting of IFN-I pathway assays.

Genes and Microbiota Interaction in Monogenic Autoimmune Disorders

“…SLE patients with an IFN signature could benefit from a human anti-IFN Ab, which competes with IFN-α binding to the receptor IFNAR2, thus preventing the activation of the IFN-α mediated pathways [ 150 ]. Interestingly, a systematic literature review by Rodríguez-Carrio et al [ 151 ] has revealed that measuring type I IFN pathway activation in these patients could potentially help in monitoring the disease activity, the prognosis, and the response to treatment, although assay harmonization and clinical validation are still needed [ 151 ].…”

Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials

“…High serum IFN-α is thought to be an hereditable risk factor for SLE, and there are multiple genetic variants in type I IFN pathway genes that are associated with SLE risk 3. Elevated type I IFN signalling, measured using IFN gene signatures (IFNGS), is associated with disease activity, organ involvement and the activity of other immune pathways in patients with SLE 4–7. Transcriptomic analyses have identified additional dysregulated biological pathways in SLE, including B-cell activating factor (BAFF) signalling and modules of genes associated with inflammation and lymphoid signalling 6.…”

Burden of systemic lupus erythematosus in clinical practice: baseline data from the SLE Prospective Observational Cohort Study (SPOCS) by interferon gene signature

“…9 Although these cytokines are produced by innate immune cells to activate the immune system and defend against viral and bacterial infections, 9 overexpression of type I IFNs occurs in patients with SLE and other autoimmune diseases, 9 10 and activation of the IFN pathway has been associated with increased SLE disease activity. [11][12][13] Type I IFN-inducible gene expression, measured using the IFN gene signature (IFNGS), provides a method to assess type I IFN pathway activation in individual patients. 14 IFNGS testing in patients with SLE has revealed a bimodal distribution of transcript scores, 15 suggesting that IFNGS-high and IFNGS-low subpopulations may differ with respect to SLE disease characteristics.…”