Development of the Digital Arthritis Index, a Novel Metric to Measure Disease Parameters in a Rat Model of Rheumatoid Arthritis

Abstract

Despite a broad spectrum of anti-arthritic drugs currently on the market, there is a constant demand to develop improved therapeutic agents. Efficient compound screening and rapid evaluation of treatment efficacy in animal models of rheumatoid arthritis (RA) can accelerate the development of clinical candidates. Compound screening by evaluation of disease phenotypes in animal models facilitates preclinical research by enhancing understanding of human pathophysiology; however, there is still a continuous need to improve methods for evaluating disease. Current clinical assessment methods are challenged by the subjective nature of scoring-based methods, time-consuming longitudinal experiments, and the requirement for better functional readouts with relevance to human disease. To address these needs, we developed a low-touch, digital platform for phenotyping preclinical rodent models of disease. As a proof-of-concept, we utilized the rat collagen-induced arthritis (CIA) model of RA and developed the Digital Arthritis Index (DAI), an objective and automated behavioral metric that does not require human-animal interaction during the measurement and calculation of disease parameters. The DAI detected the development of arthritis similar to standard in vivo methods, including ankle joint measurements and arthritis scores, as well as demonstrated a positive correlation to ankle joint histopathology. The DAI also determined responses to multiple standard-of-care (SOC) treatments and nine repurposed compounds predicted by the SMarTRTM Engine to have varying degrees of impact on RA. The disease profiles generated by the DAI complemented those generated by standard methods. The DAI is a highly reproducible and automated approach that can be used in-conjunction with standard methods for detecting RA disease progression and conducting phenotypic drug screens.

Rapid Identification and Validation of Novel Rheumatoid Arthritis Drug Treatments using an Integrative Bioinformatics Platform

“…Improvement in traditional endpoints, such as ankle joint measurements and clinical scores are indicative of reduced inflammation, erythema, and edema 32, 38 . On the other hand, improvements in the DAI, a validated, activity-dependent, and indirect readout of disease severity, may indicate improved function and mobility 35 . Functional impairments, including activity and gait measurements have been described in RA models, and have been shown to better correlate with joint damage compared to clinical scores later in disease 39 .…”

“…However, this drug is only administered at low doses clinically due to toxicities associated with their chronic use 33,34 . Therefore, it is highly unlikely for a test drug to outperform dexamethasone in the preclinical setting 35 .…”

“…Animal activity also was continuously monitored using an automated, digital platform in order to calculate the Digital Arthritis Index (DAI), an activity-dependent index of RA disease progression 35 . This index accounted for the baseline movement of the rats, which was calculated from the mobility of each animal during Days -2 to 5.…”

“…Scores for both limbs were summed during analysis. In addition to standard measures, the validated Digital Arthritis Index (DAI) was continuously collected as previously described 35 .…”

Arglabin as a potential drug in the treatment of Freund’s complete adjuvant-induced arthritis in rats

“…There are about 10 million people afflicted with RA in China [3]. The disease leads to destruction of joints, damage to cartilage and bones, thus affecting the quality of life of sufferers [4]. Arthritis mainly affects the large joints, and causes swelling and pain due to alteration in the morphology of the joints.…”