Ultrasound and fluorescence optical imaging biomarkers for early diagnosis and prediction of rheumatoid arthritis

Prevention of rheumatoid arthritis (RA) is most desirable together with curative treatment which is, however, not yet available. Today, the correct timely diagnosis and early treatment interventions to prevent disease progression remain the best options for our patients. In this thesis, I explore the diagnostic and predictive value of musculoskeletal ultrasound (MSUS) and fluorescence optical imaging (FOI) in identifying biological features on images indicative of existing or emerging joint inflammation (synovitis).

In study 1, we tested and compared the diagnostic utility of FOI with clinical examination and musculoskeletal ultrasound (MSUS) to detect active synovitis in 872 joints of 26 patients with different rheumatic diseases (46% early RA). Fluorescence optical imaging proved to be 80% sensitive and 96% specific, having a 77% positive predictive value (PPV) and 97% negative predictive value (NPV) for detecting silent synovitis.

In study 2 we showed FOI’s ability to quantify digital disease activity (DACT) scores of 1326 joints in 39 early RA patients to be 81% sensitive and 90% specific, with 96% PPV and 61% NPV. These results justify FOI use in clinical practice, to assist the rheumatologist to make an earlier diagnosis with greater confidence. Unsupervised cluster differences emerged for seropositive and seronegative RA patients showing FOI’s ability to objectively quantify hand joint inflammation using novel DACT scoring methods.

In study 3 we report good association among the two ultrasound semi-quantitative scoring (SQS) methods to that of a novel quantitative scoring (QS) measure of color Doppler pixel counts in 37 established RA patients. Although SQS well correlated with QS to assess active synovitis, the SQS methods lacked visual perceptions of raters to distinguish between grade cut-offs which may help to further revise the criteria used to objectively quantify disease activity.

In study 4, we show the value of ultrasound and immune-inflammatory biomarkers in predicting arthritis onset in individuals positive for Anti-CCP with musculoskeletal complaints at risk of RA development. We propose the recognition of a high-risk RA phase characterized by presence of certain ACPA reactivities, IL15-Rα, IL6; and ultrasound detected tenosynovitis, and possibilities to identify (low and high) risk groups for arthritis progression.

Overall, our findings on imaging contribute towards a) silent synovitis detection despite negative clinical investigation, b) objective quantitative measures to monitor the effects of RA therapy and c) early identification of certain predictive imaging and biological features/biomarkers that precede arthritis development (tenosynovitis and/or bursitis) in individuals at risk for developing RA, enabling closer monitoring and early diagnosis.

List of scientific papers

I. Detection of Clinically Manifest and Silent Synovitis in the Hands and Wrists by Fluorescence Optical Imaging. Kisten Y, Györi N, Af Klint E, Rezaei H, Levitsky A, Karlsson A, van Vollenhoven R. RMD Open. 2015 Jun 19;1(1):e000106.
https://doi.org/10.1136/rmdopen-2015-000106

II. Distinct Fluorescence Optical Imaging Patient Clusters Emerge for Seropositive and Seronegative Rheumatoid Arthritis. Kisten Y, Arnaud L, Levitsky A, Györi N, Larsson PT, Hensvold A, af Klint E, Catrina AI† and Rezaei H. †Passing/deceased. [Submitted]

III. Analysis of Correlation and Causes for Discrepancy between Quantitative and Semi-Quantitative Doppler Scores in Synovitis in Rheumatoid Arthritis. Rezaei H, Af Klint E, Hammer HB, Terslev L, D'Agostino MA, Kisten Y and Arnaud L. Rheumatology. 2017;56(2):255.
https://doi.org/10.1093/rheumatology/kew385

IV. Identification of early risk factors in a novel prediction model for ACPA positive RA. Cîrciumaru A, Kisten Y, Hansson M, Mathsson-Alm L, Joshua V, Wähämaa H, Loberg-Haarhaus M, Lindqvist J, Fei G, Vivar N, Rezaei H, af Klint E, Antovic A, Réthi B, Catrina AI¤† and Hensvold A¤. ¤Shared last authorship, †Passing/deceased. [Manuscript]