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Objectives: The aim of our work was to evaluate digital x-ray radiogrammetry (DXR) for the quantification of disease-related periarticular demineralization and computerized analysis of joint space distances (JSDA) for the measurement of joint space narrowing as a new diagnostic method for the early detection of joint-associated alterations and for monitoring disease progression in patients with rheumatoid arthritis (RA)., Materials and Methods: Digital radiographs in 313 patients with varying severity of RA were performed annually and assessed by 2 radiologists using modified Larsen and also the Sharp scores within an observation period of 3 years. The hand radiographs underwent measurements of bone mineral density (BMD) and metacarpal index (MCI) by DXR, as well as computerized JSDA at the metacarpal-phalangeal articulation (JSD-MCP) for a cross-sectional and longitudinal study design., Results: Both DXR-BMD (-29.6%; P < 0.01) and DXR-MCI (-31.0%; P < 0.01) revealed a notable reduction dependent on the severity of RA (from grade 1 to grade 5 of the modified Larsen score); the severity dependent decrease of mean JSD-MCP ranged from -31.9% (P < 0.01; Sharp erosion part) to -39.1% (P < 0.01) for the modified Larsen score. Over an observation period of 3 years, a significant decrease of DXR-BMD (-22.3%) and DXR-MCI (-23.3%) as well as JSD-MCP mean (-17.5%) was observed (P < 0.05), whereas an accentuated decline of DXR and JSDA parameters was verified for patients without disease-modifying antirheumatic drugs or methotrexate therapy., Conclusion: Computerized analysis of hand radiographs by DXR and JSDA is a promising approach to assess the severity and to monitor the progression of RA because DXR and JSDA are timely able to measure periarticular demineralization and also narrowing of JSD-MCP dependent on the severity, the medical treatment and the course of RA.