Hydroxychloroquine is a disease-modifying antirheumatic drug (DMARD) and an antimalarial. Its history began with quinine, a compound from the Cinchona tree bark used to treat fevers. Scientists later developed chloroquine and then hydroxychloroquine in 1946 as a less toxic alternative. It was approved for medical use in the United States in 1955.
Approved Medical Uses
Hydroxychloroquine is authorized for the treatment and prevention of specific types of malaria. It is effective against the forms of the parasite that live in red blood cells. However, it is not active against parasite forms in the liver and is ineffective in regions where resistance to chloroquine has been documented, limiting its use for prevention.
The medication is also a standard treatment for autoimmune disorders like systemic lupus erythematosus (SLE) and its skin-related form, chronic discoid lupus erythematosus. For patients with these conditions, it helps control disease activity and manage symptoms such as rashes and joint pain.
Hydroxychloroquine is also prescribed for rheumatoid arthritis (RA), another chronic autoimmune condition characterized by joint inflammation. As a DMARD, it aims to slow the progression of the disease and reduce pain and swelling in the joints.
Mechanism of Action
The precise way hydroxychloroquine functions is not fully resolved, but its effects are linked to its ability to accumulate inside cellular compartments called lysosomes. As a weak base, the drug gets trapped in these acidic organelles, raising their internal pH. This change interferes with cellular processes, particularly those in the immune system.
In autoimmune diseases, this interference is beneficial. By altering lysosomal pH, hydroxychloroquine hinders the ability of immune cells to process and present self-antigens—the body’s own proteins that are mistakenly targeted. This disruption dampens the overactive immune response. The drug also inhibits Toll-like receptors (TLRs), which contribute to inflammation.
Its action against the malaria parasite follows a similar principle. The parasite resides in an acidic vacuole within red blood cells where it digests hemoglobin, releasing a toxic byproduct called heme. The parasite normally neutralizes this heme by converting it into a non-toxic crystal. Hydroxychloroquine accumulates in the vacuole, raising the pH and interfering with this detoxification process, which leads to a buildup of toxic heme that kills the parasite.
Potential Side Effects and Risks
Common side effects of hydroxychloroquine are often mild. These can include gastrointestinal issues like nausea and diarrhea, as well as headaches, dizziness, and skin rashes.
A risk associated with long-term use is retinal damage, known as retinopathy, which can lead to irreversible vision loss. The risk increases with higher doses, therapy duration over five years, and in patients with pre-existing kidney or retinal problems. Therefore, regular eye examinations are standard for anyone on long-term therapy.
A rare risk involves the heart muscle, a condition called cardiomyopathy. Hydroxychloroquine can affect the heart’s electrical signaling, potentially leading to abnormal heart rhythms. Patients with pre-existing heart conditions are at a higher risk, so careful patient selection and monitoring are necessary.
The COVID-19 Controversy
At the onset of the COVID-19 pandemic, hydroxychloroquine was investigated as a potential treatment based on early lab studies suggesting it could block the SARS-CoV-2 virus from entering cells. This preliminary data, combined with public urgency, led to its widespread promotion and off-label use.
In response, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) in March 2020. This temporary measure allowed the drug to be used for certain hospitalized COVID-19 patients while more data was collected.
Subsequent large-scale clinical trials, including the RECOVERY trial in the United Kingdom, evaluated the drug’s efficacy. These trials found that hydroxychloroquine provided no benefit to hospitalized COVID-19 patients, as it did not reduce mortality, decrease the need for mechanical ventilation, or shorten hospital stays.
Based on this evidence, which also highlighted potential cardiac risks, the FDA revoked the EUA in June 2020. The scientific consensus concluded that the drug was ineffective for treating COVID-19 and could expose patients to unnecessary harm. This episode served as a case study on the importance of scientific investigation.