Polygenic Risk Score May Predict Radiographic Progression in RA

Radiographic progression susceptibility in patients with rheumatoid arthritis (RA) is linked to the polygenic risk score (PRS), according to a study published in Arthritis & Rheumatology.¹

“The goal of treatment is suppressing bone destruction and improving physical activity of the patients. The number of patients with severe radiographic progression has decreased over the last decades due to younger diagnosis and the development of several therapeutic agents,” investigators stated. “However, prevention of severe radiographic progression in a certain percentage of patients remains a challenge because of inadequate treatment response or adverse events associated with therapeutic agents.”

Using radiographic data from a genome-wide association study (GWAS) from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA), which analyzed disease susceptibility, investigators attempted to predict Sharp/van der Heijde score (SHS) changes and radiographic joint damage during the first 5 years from disease onset. The Welch’s t-test was used to evaluate PRS between the progressive group and non-progressive group, with severe progression defined as more than 35 points. Five quantile plots were created to determine risk of radiographic progression. The training set (n = 500) was validated in a testing set (n = 740).

Demographics were similar in both the training and testing sets, with the mean age of disease onset being 48.7 years in the training set and 48.5 years in the testing set. A total of 85.8% of patients were female in the training group compared with 85.6% in the testing cohort.

The 43,784 single nucleotide polymorphisms (SNPs) that made up the PRS showed significant differences between severe and non-severe progression for both training and testing sets (mean normalized PRS ± SD, 0.22 ± 1.03 vs -0.07 ± 0.98, P = 0.0064).

Those with a higher PRS were twice as likely to be classified as exhibiting severe progression when compared with those with those in the lower quintile (top quintile: OR, 95%CI, and P, 1.90, 1.26-2.86, and 0.0022).

Patients were placed into 3 groups based on age of disease onset: younger-onset (≤ 40 years), middle-onset; (> 40 years to ≤ 60 years), and elderly-onset (> 60 years). Across all groups, PRS was most significant in the younger-onset group. Radiographic progression area under the curve (AUC) was also highest among those in the younger-onset group. Independent risk factors included sex (female) (P = 0.0033), BMI (P = 0.031), PRS (P = 0.00019), and the anti-citrullinated protein antibodies (ACPAs)-positive group (P = 0.0023).

Due to the low percentage of patients receiving methotrexate and biologic disease-modifying antirheumatic drugs in this study, there is a chance that PRS predictability for radiographic progression may have been overestimated. An additional limitation was the lack of a control cohort to validate results. As a result, accuracy was determined using the training and testing groups. While this issue was mitigated by using supplementary analyses, results should be further tested using an independent control.

“The PRS constructed with GWAS meta-analysis for RA susceptibility is associated with radiographic progression in patients with RA, particularly younger age of onset RA. Furthermore, the association was independent from other clinical information,” investigators concluded. “Our study reveals that genetic profiling in polygenic rheumatic diseases has potential applications in precision medicine, which should be validated and improved in future studies.”

Reference:

Honda S, Ikari K, Yano K, et al. Polygenic risk scores are associated with radiographic progression in patients with rheumatoid arthritis [published online ahead of print, 2022 Jan 20]. Arthritis Rheumatol. 2022;10.1002/art.42051. doi:10.1002/art.42051