Hydroxychloroquine: What We Know

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Hydroxychloroquine (HCQ) is an antimalarial/disease-modifying anti-rheumatic drug (DMARD) commonly used to treat conditions such as lupus and rheumatoid arthritis by easing systemic, inflammatory symptoms.

Systemic lupus erythematosus (SLE), lupus, is a chronic autoimmune disease whereby the immune system attacks healthy cells and tissues. This causes inflammation throughout the body and can differ in appearance from patient to patient, meaning it can be difficult to diagnose. There is currently no known direct cause for Lupus, but some triggers involve genetics, exposure to sunlight, and infections which initiate relapsing. During an infection the responsive immune system may become hyperactive, leading to Lupus. [1]

Rheumatoid arthritis (RA) is also an autoimmune disease caused by the immune system targeting the synovium surrounding your joints, presenting swelling. Whilst inflammation is usually a vital process in the body, when unnecessary, the swollen synovium can cause discomfort and lead to joints being misaligned into unnatural positions. This can cause surrounding bones, ligaments and tendons to deteriorate. Although RA symptoms originate at the joints there are possible systemic symptoms such as anaemia, pulmonary fibrosis, and Felty’s syndrome. [5]

RA is a progressive disease - Arthritis (Rheumatoid ...
Rheumatoid arthritis presenting swelling of the synovial membrane [8]

Lupus and RA present similar symptoms creating initial confusion when diagnosing, but can also exist as co-morbid conditions. Some symptoms prove to be unique to each of them, such as the malar rash in lupus and rheumatoid nodules in RA. Generally, both conditions will test positive for antinuclear antibodies, but, whilst there is not a clear test for either, the presence of the anticyclic citrullinated peptide antibody indicates a high chance of RA. [1]

In an immune response, when the body detects foreign antigens, the invasive molecule is ingested via endocytosis into a membrane-bound vesicle called an endosome. These are commonly involved in the aid of intra-cellular transport during protein synthesis, creating connections between the different stages of the division of labour; particularly the vesicle creations of the Golgi body. The activation of endosomes is reliant on acidic conditions in the cell, stimulating the toll-like receptors on its membrane. This triggers the digestion process of proteins, causing inflammation. [2]

Hydroxychloroquine neutralises the pH in cells, preventing the endosomes from becoming overstimulated, and ultimately leads to a decrease in inflammatory symptoms caused by this immune response. This function has been linked to COVID-19 as some believe that the endosomes will ingest the virus so, when HCQ is in effect, the replication enzymes (RNA polymerase) will become inhibited, leading to a higher chance of asymptomatic infection or immunity. However, this theory is currently unproven. [2]

After Trump informed the public about his opinions on hydroxychloroquine there have been many influenced citizens requesting a prescription from their GPs, ‘just in case’ it provides immunity from COVID-19. However, what both parties fail to recognise is the impact this has on the 5 million American patients with necessary repeat prescriptions. Some shortages of the drug have already been reported around the country, creating uneasiness in those who have been taking the drug both long and short term. Rationing HCQ is not advised due to a constant dose required for optimum efficacy, leading to a higher demand for drug production. [4]

The severity of risks from Covid-19 is heightened by any underlying/current infection so, without access to the appropriate healthcare, patients have a further increased possibility of experiencing life threatening symptoms.

There have been recent reports released concerning the increased risk of mortality when taking the drug, concluded after the comparison of the death to the survival rate of 96,000 patients in 671 hospitals around the world. As this was not a drug trial there were no control factors such as age, gender or illness, but it is still shown that 1 in 4 patients died whilst taking hydroxychloroquine and an antibiotic simultaneously, and 1 in 6 taking HCQ/chloroquine alone. Whilst it is possible that the drug-drug interaction enhanced the risk, it is clear that the HCQ/chloroquine enhances death rate compared to 1 in 11 in patients who did not take the drug; almost doubling the likelihood. [4]

There has also been evidence presenting prolonged risks of cardiac arrhythmia, hydroxychloroquine- induced myopathy, neuromyopathy and retinal toxicity; the second of which is rare but fatal. [6]

Cardiomyopathy - Symptoms and causes - Mayo Clinic
Hypertrophic cardiomyopathy presenting an abnormal increase in thickness [7]

HCQ initiates phospholipidosis (accumulation of phospholipids in the cytoplasm), by inhibiting the lysosomal phospholipase enzymes and preventing cleavage. This causes structures such as myeloid bodies and curvilinear bodies to remain in the cytoplasm, leading to cytoplasmic vacuolation. Ultimately, the cardiac myofibril arrangement becomes disrupted, cell hypertrophy occurs, and then excess cardiac scar tissue is formed (fibrosis) leading to an abnormal thickening of the heart. [6]

This can prove to be fatal due to weakened contractions, leading to QTc prolongation, i.e. a lack of regular intrinsic rhythmicity (cardiac arrhythmia), and prolonged risk of heart failure.

Results of hydroxychloroquine’s effectiveness will become clear following the randomised, controlled drug trials involving healthy NHS workers in contact with infected patients. However, ultimately, the unnecessary and unproven use of hydroxychloroquine will put strain on those who rely on the drug for comfort and suppression of symptoms.


References

  1. ‘Lupus’, Mayo Clinic, Oct. 25, 2017
  2. Lauren Gelman, ‘A Rheumatologist Explains Why a Hydroxychloroquine Shortage Is Terrifying to Lupus and Rheumatoid Arthritis Patients’, Creaky Joints, March 22, 2020
  3. Muthukrishan, Roukoz, Grafton, Jessurun, Colvin-Adams, ‘Hydroxychloroquine-Induced Cardiomyopathy’, American Heart Association, March 1 2011
  4. ‘Hydroxychloroquine: Trump’s Covid-19 ‘cure’ increases deaths, global study finds’, The Guardian, May 22 2020
  5. ‘Rheumatoid arthritis’, NHS Inform, Feb. 14 2020
  6. Di Girolamo, Claver, Olivé, Salazar-Mendiguchía, Mantio, Cequier, ‘Dilated Cardiomyopathy and Hydroxychloroquine-induced Phospholipidosis’, Revista Española de Cardiología, April 17, 2017
  7. ‘Cardiomyopathy’, Mayo Clinic, Jan. 23, 2019
  8. ‘RA is a progressive disease’, MedBraodcast

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