Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease affecting 1% of the
population. Aggressive treatment is a fundamental therapeutic strategy to improve disease-related
outcomes and cardiovascular disease, which contributes to excess mortality in RA. Thus, therapeutics
targeting novel pathways that treat RA and reduce cardiovascular risk are needed. A potential target is
blocking the proinflammatory, immunogenic, and proatherogenic consequences of isolevuglandins
(isoLGs).
IsoLGs are highly reactive dicarbonyl products of oxidative stress that bind covalently to proteins
causing conformational changes rendering them immunogenic and proinflammatory. Two decades of
work at Vanderbilt led to the identification of 2-hydroxybenzylamine (2-HOBA) as a highly effective
scavenger of reactive dicarbonyls such as isoLGs. Scavenging reactive dicarbonyls is preferable to using
antioxidants because reactive oxygen species are necessary for normal cellular function. In animal models
of autoimmunity, hypertension, and atherosclerosis 2-HOBA reduced inflammation, autoantibodies,
blood pressure, and atherosclerosis, and in human phase 1 clinical studies in healthy volunteers 2-HOBA
was well tolerated.
We propose a phase 2 study to determine 2-HOBA’s tolerability, safety, and effect on isoLG-
adducts, inflammation and blood pressure in RA patients. Twenty-eight subjects will be randomized to
750mg 2-HOBA or matching placebo three times a day for 12 weeks (14 per group). A visit at week 16 will
assess for persisting effects after a 4-week washout. Aim 1 will compare tolerability and adverse events
in active and placebo arms. Aim 2 will compare changes in cellular and plasma isoLG-adducts, markers of
inflammation, DAS28 score, and 24-hour blood pressure in active and placebo arms. This pilot study will
inform the feasibility and design of future studies to examine the efficacy of 2-HOBA in RA patients.