The American College of Rheumatology (ACR) summarized a report regarding the cardiac toxicity associated with the long-term use of antimalarial drugs, including hydroxychloroquine (HCQ) and chloroquine (CQ). The full paper was published in Arthritis & Rheumatology.

Although HCQ and CQ are well-established therapies for systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other rheumatic and dermatologic diseases, their experimental use in the treatment of COVID-19 has led to concerns about potential toxicities. In particular, the associated risks for corrected QT interval (QTc)-prolongation and torsade de pointes (TdP) have been highlighted.

To address these concerns and summarize the current understanding of HCQ/CQ, a working group of medical practitioners developed consensus-based opinions and recommendations. The working group included 8 rheumatologists, 2 dermatologists, and 2 expert electrophysiology cardiologists. The committee participated in 2 virtual conferences and reviewed published studies on HCQ/CQ and cardiac toxicity.


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The resulting report included the following primary components: a summary of QTc prolongation and TdP; a summary of independent risk factors for QTc prolongation; evidence for QTC prolongation with HCQ/CQ use; evidence for cardiac deposition disease with long-term HCQ/CQ use; suggestions for treating physicians; and directions for future research.

Summary of QTc Prolongation and TdP

  • The QT interval is an electrocardiography (ECG) measurement that includes the beginning of the QRS complex to the end of the T wave, representing the time required for ventricular depolarization and repolarization.
  • TdP is a form of ventricular tachycardia characterized by “twisting” of the QRS complexes around the isoelectric line.
  • Prolonged QTc increases the risk for TdP.
  • Prolonged QTc also increases the risk for sudden cardiac death, possibly as a result of its association with TdP.

Independent Risk Factors for QTc Prolongation

  • Both RA and SLE are risk factors for atherosclerotic cardiovascular disease (CVD).
  • Certain observational studies have indicated that HCQ/CQ use may decrease the risk for CVD in RA and SLE by reducing disease severity.
  • In patients with SLE, the presence of anti-Ro 52 antibodies may increase the risk for QTc prolongation.
  • Additional risk factors for prolonged QTc include the female sex; older age; heart disease; use of more than 1 QTc-prolonging medication; severe acute illness (potentially including COVID-19); congenital long QT syndrome; electrolyte abnormalities; alcoholic liver disease; hypothyroidism; obesity; and diabetes mellitus.

QTc Prolongation With HCQ/CQ Use

  • Several studies have indicated an association between HCQ use and QTc prolongation. However, the association is minor and does not necessarily confer increased risk for death.
  • Documented arrhythmia as a result of QTc prolongation is rare.
  • Patients with other QTc prolongation risk factors are at increased risk for HCQ/CQ-associated QTc prolongation.

Cardiomyopathy With HCQ/CQ Use

  • Long-term HCQ/CQ use may lead to accumulation in the lysosomes of cardiac myocytes, which in turn can cause arrhythmia and infiltrative cardiomyopathy.
  • Cessation of HCQ/CQ may improve cardiomyopathy, though atrioventricular conduction disease cannot be reversed once acquired.
  • Cardiomyopathy with HCQ/CQ use is considered a rare event, but it may be underreported in literature.

Suggestions for Treating Physicians

  • ECG monitoring is not part of standard practice when HCQ/CQ is prescribed.
  • A baseline ECG is recommended among patients with additional independent risk factors for QTc prolongation.
  • Concomitant medications known to prolong the QTc interval should be avoided.
  • If patients show symptoms suggestive of an arrhythmia, an ECG may be obtained.
  • Patients with long-term HCQ/CQ use should be monitored closely.

Directions for Future Research

  • The working group acknowledged limitations in the current literature, which included small cohort size and retrospective design.
  • In addition, it can be difficult to determine whether deaths due to CVD were a direct result of QTc prolongation.
  • There is a need for prospective data on the risk for QTc prolongation on the incidence of cardiac toxicity. Long-term studies with regular ECG monitoring must be undertaken to inform this gap.

Conclusions

Both HCQ and CQ are important therapeutic options in the management of SLE and RA, as these drugs are known to substantially reduce disease activity. Cardiac toxicity, as a result of HCQ/CQ use, is rare, though the risk increases with prolonged exposure. A careful risk/benefit analysis should be conducted by providers prior to HCQ/CQ use. Further, consistent ECG monitoring is recommended if the patient has other risk factors for cardiac events.

“Increased clinical awareness of the potential for cardiac toxicity, both pro-arrhythmic

and associated with long-term use, is essential as HCQ and CQ remain foundational medications in the treatment of autoimmune rheumatic diseases, and their proven benefits should be weighed along with these risks,” the group noted.

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 

Reference

Desmarais J, Rosenbaum JT, Costenbader KH, et al. American College of Rheumatology white paper on antimalarial cardiac toxicity. Arthritis Rheumatol. Published online October 26, 2021. doi:10.1002/art.41934