Background/Purpose: Hydroxychloroquine (HCQ) is commonly prescribed for patients with rheumatoid arthritis (RA). Cardiotoxicity is a rare but potentially life-threatening side effect of HCQ and may present as a cardiomyopathy resulting in congestive heart failure (HF). The evidence of cardiotoxicity associated with the use of HCQ largely relies on case reports and case series while large cohort studies on the subject are lacking. In this population-based cohort study, we aimed to examine the association between exposure to HCQ and incidence of HF in patients with RA.

Methods: A population-based incidence cohort of RA patients aged ≥18 years (1987 ACR criteria first met between 1/1/1980 and 1/1/2008) with no history of HF was followed until onset of HF (defined by Framingham criteria), death, or 1/1/2008. We collected data on RA characteristics, cardiovascular (CV) risk factors including current smoking, obesity, hypertension, antihypertensive use, dyslipidemia, diabetes mellitus, and the presence of coronary heart disease (CHD) defined as any of the following: angina pectoris, coronary artery disease, myocardial infarction (including silent events), and coronary revascularization procedures (i.e., coronary artery bypass graft, percutaneous angioplasty/stenting, and atherectomy).

Results: The study included 795 RA patients [mean age 55.3 years, 69% women, 66% rheumatoid factor (RF)-positive]. During the mean followup of 9.7 years, 92 patients developed HF. There was no overall increase in risk of HF in patients who used HCQ at any time during the follow up (HR 0.9, 95%CI 0.6-1.4) or in current users of HCQ vs non-users (HR 1.0, 95%CI 0.5-1.8). However, compared to non-users, patients with RA who used HCQ for >14 years had over 3-fold increase in risk of developing HF (HR 3.61; 95%CI 1.23-10.63). The association remained statistically significant when additionally adjusting for corticosteroid use (p=0.036), CV risk factors and CHD (p=0.049). The association remained significant in the subset of patients without CHD when censoring those who develop CHD during follow-up (p=0.038). HCQ users were equally likely to develop HF with preserved or reduced ejection fraction.

Conclusion: Prolonged use of HCQ in RA is associated with increased risk of incident HF. Underlying mechanisms for this association require further elucidation.