Hydroxychloroquine Re-Examined: A Legacy Drug Facing Modern Challenges

Abstract

Hydroxychloroquine (HCQ) has in many ways been a pharmacological chameleon, with changing formulations and evolving clinical uses, from its early role as an antimalarial to being a cornerstone treatment in rheumatic disease. Targeted therapies have changed the treatment landscape of these conditions over recent decades. This raises the question of the long-term therapeutic role of HCQ and its limitations, which we will aim to explore some of these questions.

The story of HCQ's origin is somewhat disputed; however, the first claimed use of quinine (from which HCQ is derived) was in the 1600s when bark powder from the Cinchona tree in South America was used to treat febrile illness [1] was then widely distributed across Europe for its medicinal properties.

Over the next few centuries, various alkaloids were extracted and used primarily as an anti-malarial, quite extensively in World War II in the form of chloroquine, which was synthesized in the 1930s [1]. It was at this time that recognition was made of its clinical utility for inflammatory arthritis and lupus; however, concerns about toxicity led to the development of HCQ in 1950 as a less toxic alternative.

Despite its broad use, the mechanism of action of HCQ is still not well understood, although there are several key mechanisms by which it is thought to exert its therapeutic actions [2].

HCQ is a weak base and is known to accumulate in acidic lysosomes where it causes an increase in pH that impairs key processes including autophagy and antigen processing. Inhibition of Toll-like receptor (TLR) signaling (particularly TLR7 and 9) through various mechanisms has also been postulated as a mechanism for its anti-inflammatory effect with downstream effects related to inhibition of various pro-inflammatory cytokines.

Rheumatologists are most familiar with HCQ use in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

In the recent EULAR recommendations in 2023 for the management of SLE [3], HCQ is recommended for all patients unless contraindicated.

These recommendations are supported by evidence of benefit across broad outcomes including patient survival, organ damage, flare rates, musculoskeletal manifestations, and cancer risk [4].

Recently, the ubiquitous use of HCQ in SLE has been questioned, with a review by Caravaca-Fontan et al. highlighting the paucity of evidence for HCQ in lupus nephritis (LN) [5], in particular, for remission induction, flare reduction, and kidney function recovery. This review also cited limitations of current evidence, including small study populations with predominantly observational and retrospective data that were prone to bias.

The same authors argued a need for further research on HCQ use for LN, in light of modern induction and maintenance protocols [6]. Previous studies did not consider factors such as immunological and clinical remission and lacked data on medication adherence. Notably, there were no randomized controlled trials in adults with LN that demonstrate an additional benefit of HCQ when treated according to the standard of care.

In addition, toxicity risk is increased in those with impaired kidney function, and standard dosing of HCQ may not be adequate for LN with an increased risk of relapse. In the current era of targeted therapies, it was argued that unrestricted recommendations for HCQ did not make sense. The authors did acknowledge the use in other disease manifestations, such as cutaneous lupus, anti-phospholipid syndrome, and pregnancy.

A rebuttal of this commentary was subsequently published by Pappa et al. in the same journal [7], who argued that HCQ should be used in all patients with LN, reminding us that LN is part of a systemic disease and requires a holistic approach. Numerous observational studies were outlined that associated the use of HCQ with higher rates of response, including renal remission, reduced risk of renal flares, lower rates of CKD, and ultimately a lower risk for death. The lack of RCT data was acknowledged; however, data was drawn from the Canadian HCQ study group conclusions from > 30 years ago that patients randomized to continued HCQ treatment had a 74% reduction in risk of nephritic flares compared to patients who withdrew. The authors postulated that the unique properties of HCQ allow it to be immunosuppressive and nephroprotective and may help in the tapering of other immunosuppressants.

In RA there is limited recent literature on HCQ. A systematic review in 2020 identified only six studies, with RCT data limited to small patient populations. The available data does not support the use of HCQ as monotherapy, but does show some benefit in combination with other conventional synthetic DMARDs [8]. There is also data to suggest potential cardiovascular benefit of HCQ in RA patients, with improvements in lipid profiles and a reduced incidence of diabetes; however, this was based largely on observational studies [9].

HCQ use has also been extrapolated to other connective tissue diseases such as Sjogren's disease. It is estimated that 25%–50% of patients with primary Sjogren's disease are taking HCQ [10], however recommendations for its use in guidelines are based largely on expert opinion and personal experience. While there are guideline-based recommendations for manifestations such as musculoskeletal/articular pain, fatigue, and hypergammaglobulinaemia, supportive data is lacking, and the exact mechanism and clinical benefits are still unclear [10].

Only three RCTs have investigated the benefits of HCQ in primary Sjogren's disease for oral and ocular involvement [10] with all three trials failing to show a benefit. The JOQUER trial also showed no benefit in extraglandular disease, however subsequent subgroup analysis based on symptom burden was able to demonstrate some between-group differences. These trials have been limited by the challenge of finding meaningful trial endpoints in a heterogenous disease like Sjogren's.

HCQ does have a well-defined role in primary and secondary prevention of congenital atrioventricular block in women of reproductive age with anti-Ro/SSA and anti-La/SSB antibodies [11].

In primary antiphospholipid syndrome (APS), HCQ is often used as an additional treatment in difficult-to-treat disease, although data is scarce. Its use in refractory obstetric antiphospholipid syndrome has demonstrated positive effects, with an increase in live birth rates when used alongside standard of care (low dose aspirin and low molecular weight heparin) [12].

Whilst generally recognized as a safe and well tolerated drug, there are certain toxicity considerations that often raise concern for clinicians and patients.

Ocular toxicity is the most well recognized complication of long-term HCQ use with the potential for significant morbidity.

The main risk factors for HCQ-related retinopathy include treatment duration and cumulative dose, with age and renal impairment carrying additional risk. The risk is thought to be low in patients on treatment < 5 years, and an increased risk is associated with doses > 5 mg/kg/day (actual body weight) which is the generally accepted dosing recommendation [13].

Prevalence data of HCQ retinopathy is inconsistent, ranging anywhere from < 1% up to 20% (in patients on long term treatment), mostly based on retrospective data [14]. These higher reported prevalence rates arguably do not reflect the anecdotal experience of clinicians who use HCQ frequently.

The prevalence of cardiac toxicity is unclear; however, HCQ has been associated with conduction abnormalities, most commonly QT prolongation. Some of the recent literature was published in the context of the COVID-19 pandemic, when it was often used in conjunction with other QT-prolonging medications such as azithromycin. This suggests the role of potential confounders, including the cardiac effects of COVID infection in these studies. Reassuringly, in a large SLE and RA cohort of over 500 patients, HCQ use was not associated with an increased QT interval [15]. Some recommendations have advised routine baseline and serial ECG monitoring in patients commencing HCQ, which in practical terms is unlikely to be feasible in standard practice settings.

The story of HCQ can be seen as symbolic of medical advancement, with hopeful innovation often tempered by caution and conflicting evidence.

Its low cost, availability, and relative safety have allowed HCQ to remain in the treatment paradigm; however, its broad mechanisms may also be a weakness, as the push for more precise and targeted therapies will continue to challenge its role, and like any existing therapy, we must continue to ask questions to qualify its ongoing use as standard of care.

Both authors contributed equally to this manuscript.

The authors declare no conflicts of interest.