Current Drug Therapy

Hydroxychloroquine: An old drug with new relevance

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AREAS OF UNCERTAINTY

Benefit in preclinical lupus?

Hydroxychloroquine has a consistently profound effect on outcomes in systemic lupus erythematosus. These findings, in addition to the more widespread use of antibody screening, have led to suggestions that hydroxychloroquine could be of benefit even before systemic lupus erythematosus is diagnosed.

A study in US military personnel found that patients taking hydroxychloroquine experienced a significantly longer lag time between first reported clinical symptoms of lupus and official diagnosis compared with matched controls who also went on to develop the disease, averaging 1.08 vs 0.29 years to disease classification.43 Those who used hydroxychloroquine also had lower rates of autoantibody accumulation. Therefore, hydroxychloroquine could be of benefit in carefully selected candidates at high risk of developing systemic lupus erythematosus.

The beneficial effects of hydroxychloroquine on patients with lupus and rheumatoid arthritis, in terms of primary measures of disease activity and secondary outcomes, were discovered fortuitously and were not the original intended targets of the drug. Because of its versatility, there are numerous other disease states in which hydroxychloroquine has shown a degree of benefit or has shown a potential for benefit.

Antiviral activity?

It has been suggested that antimalarial drugs could serve as adjunctive therapies against filoviruses such as Marburg and Ebola. There is a small body of in vitro and in vivo evidence that hydroxychloroquine could temper severe systemic inflammatory responses to filoviruses both through dysregulation of lysosomes and lysosomal pH (filoviruses have a pH-dependent mechanism of action) and through decreased production of tumor necrosis factor alpha and interferons. Heavy burdens of interferons and tumor necrosis factor alpha are associated with increased mortality rates in those infected with filoviruses.44

Antineoplastic activity?

Hydroxychloroquine has undergone in vitro testing as an adjunct to cancer therapies. There are several mechanisms by which it is theorized that hydroxychloroquine could target malignant cells, including inhibition of multidrug resistance pumps or autophagy, improvement of chemotherapy cell penetration, potentiation of presentation of major histocompatibility complexes, or even intercalation directly into DNA.45,46 However, it can also impair natural anticancer immunity and may allow cancer cells better nutrient supply through vascular effects.

In vitro studies have shown tumoricidal effects in lymphoma and melanoma, and inhibition of growth in lung, colon, breast, cervix, larynx, liver, and prostate cancers. In vivo studies have shown that hydroxychloroquine in high doses can prolong survival in glioblastoma.45

Unfortunately, all of these theorized or observed effects are dose-dependent and likely require doses that exceed currently recommended maximums.

Negative chronotropic effect?

Hydroxychloroquine has been found to decrease the resting heart rate in a cumulative dose-dependent fashion.47 Further, hydroxychloroquine has been known to increase digoxin levels, and the medications should not be used in combination.1

Whether the decrease in resting heart rate is associated with harm or benefit and whether the effect is significant enough to be considered when implementing therapy remain unanswered and deserve further investigation, as does the primary use of hydroxychloroquine for beneficial lipid and glucose reduction in patients who are otherwise healthy.

CASE CONCLUSION

The patient described at the beginning of this article was provided with information on the risks and benefits of hydroxychloroquine for treatment of her arthritis and rash suggestive of mild systemic lupus, and she opted to begin therapy. Her baseline eye screening was within normal limits. Based on her weight of 62 kg, she was started on 300 mg of hydroxychloroquine daily.

She had no significant adverse effects from the medication and reported slow improvement in her rash and joint complaints over the next 2 months. She remained on hydroxychloroquine over the next year without adverse effects or new evidence of autoimmune disease.

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