To operationalize this, a tiered risk-stratification algorithm is proposed wherein high-risk patients include those with long-standing RA (greater than 10 years), persistently elevated inflammatory biomarkers such as IL-6 and CRP, presence of pathogenic somatic mutations, prior exposure to high cumulative doses of MTX or JAK inhibitors, or existing cytopenias. This evidence concerns the gene IL6 and rheumatoid arthritis.