2-Hydroxybenzylamine acetate (2-HOBA) in rheumatoid arthritis: a randomized phase 2 clinical trial

Patients with rheumatoid arthritis (RA) have increased oxidative stress, which may contribute to inflammation and elevated blood pressure. 2-hydroxybenzylamine acetate (2-HOBA) scavenges reactive downstream oxidative stress products, including isolevuglandins (IsoLGs), which covalently bind proteins and alter their structure. This pilot study evaluated the safety and tolerability of 2-HOBA, its effect on IsoLG-protein adducts, and potential effects on disease activity and blood pressure in RA. We conducted a single-center, randomized, double-blind, parallel-group, phase 2 clinical trial. Patients with RA ( n = 32) were randomized to receive 2-HOBA 750 mg or matching placebo orally three times daily for 4 weeks. Primary outcomes were safety, tolerability, and change in cells with IsoLG-protein adducts. Exploratory outcomes included changes in disease activity and blood pressure. Linear mixed-effects models assessed treatment effects of 2-HOBA versus placebo. The modified intention-to-treat population included 30 participants (2-HOBA n = 16, placebo n = 14). 2-HOBA was safe and well tolerated, with similar adverse event rates between groups. Compared with placebo, 2-HOBA did not significantly alter cells with IsoLG-protein adducts (treatment effect 3.4%; 95% CI, -4.0 to 10.9; p = 0.35) or plasma IsoLG-lysine adducts (− 2.14 pg/mg protein; 95% CI, -5.01 to 0.73; p = 0.14). No significant effects were observed on DAS28-CRP or blood pressure ( p > 0.05); however, swollen and tender joint counts and systolic blood pressure showed small, non-significant improvements with 2-HOBA. 2-HOBA was safe and well tolerated in patients with RA. Over the 4-week treatment period, no statistically significant changes in cellular or plasma IsoLG-protein adducts or exploratory clinical outcomes were observed. ClinicalTrials.gov, NCT05274243. Registered March 1, 2022. https//clinicaltrials.gov/ct2/show/NCT05274243.