Hydroxychloroquine (HCQ) is an oral medication with both antimalarial and immunomodulatory properties. Developed as a less toxic derivative of chloroquine it has been in continuous clinical use since the 1950s. HCQ is now used primarily to treat autoimmune conditions including systemic lupus erythematosus (SLE) and rheumatoid arthritis.

Drug Class

HCQ belongs to the 4-aminoquinoline class of drugs. The drug was developed as an antimalarial but has since found its primary clinical role in rheumatology and dermatology. Unlike classic immunosuppressants such as methotrexate or azathioprine, HCQ does not broadly suppress immune function but rather modulates specific immune cell signalling pathways. This makes it one of the safest long-term disease-modifying drugs available for autoimmune conditions with a favourable safety profile supported by decades of clinical experience.

Medical Uses

Doctors prescribe hydroxychloroquine as:

• Malaria prevention and treatment: HCQ is used for prophylaxis and treatment of Plasmodium vivax and Plasmodium malariae malaria; chloroquine-resistant Plasmodium falciparum is not responsive to HCQ

• Systemic lupus erythematosus (SLE): HCQ is the cornerstone drug for SLE; it reduces lupus flares and organ damage 

• Rheumatoid arthritis: Used as a disease-modifying antirheumatic drug (DMARD) and frequently combined with methotrexate and sulfasalazine in triple therapy

• Sjögren's syndrome: Reduces sicca symptoms and systemic disease activity

• Cutaneous lupus and discoid lupus: HCQ reduces sun-sensitive rashes and skin manifestations

• Antiphospholipid syndrome: HCQ reduces thrombosis risk and pregnancy complications.

How Hydroxychloroquine Works in the Body

HCQ accumulates in lysosomes - acidic compartments within immune cells involved in antigen processing and cytokine signalling. By raising the pH inside lysosomes, HCQ disrupts the processing of autoantigens, reducing activation of autoreactive T and B lymphocytes. It also inhibits Toll-like receptor (TLR) 7 and TLR9 signalling - the pathways by which immune cells detect nucleic acid-based danger signals and trigger inflammatory responses. The result is reduced production of inflammatory cytokines including type I interferons, TNF-alpha and interleukins - precisely the cytokines that drive lupus and rheumatoid arthritis disease activity.

Long-term Use: What Patients With Autoimmune Conditions Should Know

HCQ is intended for long-term, often lifelong use in conditions like SLE. It is not a drug taken only when symptoms worsen but it works preventively by continuously modulating immune activity. Stopping HCQ in SLE patients even during periods of clinical remission, significantly increases the risk of lupus flares within months. The American College of Rheumatology and the Indian Rheumatology Association both recommend continuing HCQ indefinitely in SLE patients who tolerate it. 

Side Effects: From Mild to Rare but Serious

Common and generally mild side effects include:

• Nausea, vomiting, and abdominal discomfort 

• Headache 

• Skin rash and pigmentation changes 

• Hair thinning.

Serious but uncommon side effects include:

• Retinal toxicity 

• Cardiac toxicity like QTc prolongation and very rarely cardiomyopathy

• Haematological effects including neutropenia, thrombocytopenia and aplastic anaemia are rare

• Neuromuscular toxicity like proximal myopathy and peripheral neuropathy; very rare at standard doses.

Eye Safety - Why Regular Eye Tests Are Required

HCQ can cause irreversible retinal toxicity (damage to the photoreceptors in the macula) with cumulative high-dose exposure. The risk is low with doses at or below 5 mg/kg/day and during the first 5 years of treatment but rises significantly after 10 years of use and with total cumulative doses exceeding 1000 grams. Early retinal toxicity is asymptomatic and by the time visual symptoms appear like reduced central vision, colour discrimination or visual field defects damage is often advanced and irreversible.

The Royal College of Ophthalmologists and the American Academy of Ophthalmology recommend a baseline eye examination within 1 year of starting HCQ followed by annual screening after 5 years. Recommended tests include fundus autofluorescence (FAF), optical coherence tomography (OCT) and automated visual field testing (10-2). 

Who Should Not Take Hydroxychloroquine?

A certain group of people should use hydroxychloroquine cautiously. They are:

• Known hypersensitivity to HCQ or 4-aminoquinolines

• Pre-existing retinal or macular disease 

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency as HCQ can precipitate haemolytic anaemia

• Pre-existing QTc prolongation or significant cardiac arrhythmia 

• Patients on QTc-prolonging medications as the combination can increase the risk of potentially fatal ventricular arrhythmias (Torsades de Pointes).

Drug Interactions to Watch Out For

Key interactions are:

• QTc-prolonging drugs like Antiarrhythmics (amiodarone, sotalol), some antipsychotics (haloperidol, quetiapine), some antibiotics (azithromycin, moxifloxacin) all additive risk of dangerous cardiac arrhythmia

• Magnesium and aluminium antacids reduce HCQ absorption

• Metformin

• Digoxin

• Cyclosporin.

HCQ and COVID-19 – What Evidence Actually Shows

During the COVID-19 pandemic, HCQ attracted intense global attention as a potential antiviral treatment. In India, ICMR issued guidelines in 2020 recommending HCQ prophylaxis for healthcare workers and household contacts of confirmed COVID-19 cases. Multiple subsequent large randomised controlled trials including the RECOVERY trial in the UK found no significant benefit of HCQ in hospitalised COVID-19 patients for reducing mortality, intensive care admission or duration of mechanical ventilation. HCQ is not currently recommended for COVID-19 prevention or treatment by the WHO, ICMR, or any major national health authority.

FAQs

1. What conditions is hydroxychloroquine prescribed for?

   HCQ is prescribed for systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren's syndrome, cutaneous lupus, discoid lupus, antiphospholipid syndrome and malaria prophylaxis and treatment. In SLE, it is considered a cornerstone treatment recommended for all patients unless contraindicated, given its proven ability to reduce flares, organ damage and mortality over long-term use.

2. Can hydroxychloroquine damage the eyes?

   Yes HCQ can cause retinal toxicity specifically Bull's eye maculopathy, with prolonged high-dose use. The risk is low in the first 5 years and at doses at or below 5 mg/kg/day but increases significantly with cumulative dose exceeding 1000 grams and duration beyond 10 years. Therefore annual ophthalmological screening after 5 years of use is essential to detect toxicity early.

3. How long does it take for hydroxychloroquine to work for lupus?

   HCQ acts slowly. For lupus, clinical improvement in skin rashes, joint pain, and fatigue typically takes 4 to 12 weeks to become apparent and the full benefit for reducing flares and organ damage accumulates over months to years. HCQ's value lies in its cumulative protective effect on long-term disease activity rather than as a treatment for acute flares. Maximum benefit typically occurs at 6 to 12 months of consistent use.

4. Is hydroxychloroquine safe to take for many years?

   Yes  HCQ has one of the best long-term safety profiles of any disease-modifying drug, which is why it is recommended for indefinite use in SLE. The principal concern with long-term use is retinal toxicity, which is why regular ophthalmological screening is required. 

5. What eye tests are needed for people on long-term hydroxychloroquine?

   The recommended monitoring protocol are: 

   • Optical coherence tomography (OCT) of the macula - highly sensitive for detecting early photoreceptor damage

   • Fundus autofluorescence (FAF) - detects abnormal lipofuscin accumulation in the retinal pigment epithelium

   • 10-2 automated visual field testing - assesses the central 10 degrees of vision where early HCQ toxicity manifests.

    A baseline examination should be conducted within 1 year of starting HCQ, with annual screening after 5 years of use.

6. Can hydroxychloroquine cause skin problems or hair loss?

   Skin side effects are uncommon but documented. A skin rash occurs in a minority of patients and may require discontinuation. Bluish-grey pigmentation of the skin, mucous membranes and nails has been reported with prolonged use. Hair thinning is occasionally reported. 

7. Is hydroxychloroquine safe during pregnancy?

   Yes HCQ is one of the safest immunomodulatory drugs in pregnancy. Continuing HCQ throughout pregnancy in SLE patients is recommended because stopping it significantly increases the risk of lupus flares, which are associated with serious maternal and foetal complications. HCQ does cross the placenta but extensive data have not shown increased rates of birth defects, pregnancy loss or neonatal harm. 

8. Does hydroxychloroquine affect the heart?

   At standard doses, HCQ's cardiac effects are generally benign and it may be cardioprotective in lupus patients through its antiplatelet and lipid-lowering effects. However HCQ can prolong the QTc interval, increasing the risk of ventricular arrhythmias when combined with other QTc-prolonging drugs. An ECG before starting HCQ and periodic monitoring are advisable in patients with cardiac disease.

9. Can hydroxychloroquine be stopped suddenly or must it be tapered?

   HCQ does not require tapering to avoid a withdrawal syndrome. It can technically be stopped abruptly without physiological harm. However, in SLE patients, stopping HCQ suddenly significantly increases the risk of disease flares, which can be severe and difficult to control. Any decision to stop or reduce HCQ in lupus or rheumatoid arthritis should be made in consultation with the treating rheumatologist, with a plan for alternative disease management in place.

References

1. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386–94. https://doi.org/10.1016/j.ophtha.2016.01.058

2. Gunes A, Dastoorpour M, Sander A, et al. RECOVERY Collaborative Group: effect of hydroxychloroquine in hospitalised patients with COVID-19. N Engl J Med. 2020;383(21):2030–40. https://doi.org/10.1056/NEJMoa2022926

3. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69(1):20–8. https://doi.org/10.1136/ard.2008.101766

4. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 2006;54(11):3640–7. https://doi.org/10.1002/art.22159

5. Indian Rheumatology Association. Clinical practice guidelines for the management of systemic lupus erythematosus in adults. Int J Rheum Dis. 2022;25(11):1201–32. https://doi.org/10.1111/1756-185X.14426