Fractal analysis of perfusion imaging in synovitis: a novel imaging biomarker for grading inflammatory activity based on assessing angiogenesis

Objectives The mutual and intertwined dependence of inflammation and angiogenesis in synovitis is widely acknowledged. However, no clinically established tool for objective and quantitative assessment of angiogenesis is routinely available. This study establishes fractal analysis as a novel method to quantitatively assess inflammatory activity based on angiogenesis in synovitis. Methods First, we established a pathophysiological framework for synovitis including fractal analysis of software perfusion phantoms, which allowed to derive explainability with a known and controllable reference standard for vascular structure. Second, we acquired MRI datasets of patients with suspected rheumatoid arthritis of the hand, and three imaging experts independently assessed synovitis analogue to Rheumatoid Arthritis MRI Scoring (RAMRIS) criteria. Finally, we performed fractal analysis of dynamic first-pass perfusion MRI in vivo to evaluate angiogenesis in relation to inflammatory activity with RAMRIS as reference standard. Results Fractal dimension (FD) achieved highly significant discriminability for different degrees of inflammatory activity (p<0.01) in software phantoms with known ground-truth of angiogenic structure. FD indicated increasingly chaotic perfusion patterns with increasing grades of inflammatory activity (Spearman's rho=0.94, p<0.001). In 36 clinical patients, fractal analysis quantitatively and objectively discriminated individual RAMRIS scores (p <= 0.05). Area under the receiver-operating curve was 0.84 (95% CI 0.7 to 0.89) for fractal analysis when considering RAMRIS as ground-truth. Fractal analysis additionally identified angiogenesis in cases where RAMRIS underestimated inflammatory activity. Conclusions Based on angiogenesis and perfusion pathophysiology, fractal analysis non-invasively enables comprehensive, objective and quantitative characterisation of inflammatory angiogenesis with subjective and qualitative RAMRIS as reference standard. Further studies are required to establish the clinical value of fractal analysis for diagnosis, prognostication and therapy monitoring in inflammatory arthritis.