How is hydroxychloroquine used for 2 years, how is cardiotoxicity? The latest research gives the answer

*For medical professionals only to read and refer to the rational use of very critical

hydroxychloroquine pharmacological effects are mainly to inhibit the processing and presentation of their own antigens, while inhibiting the chemotaxis of polymorphonuclear leukocytes, blocking the biosynthesis of prostaglandins, and

exerting its anti-inflammatory effects
.
In addition, its anticoagulant effect can be achieved by reducing erythrocyte deposition and inhibiting platelet aggregation and adhesion
.

Therefore, hydroxychloroquine is commonly used in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but its side effects have long plagued people, including neurological, musculoskeletal, visual impairment, skin, blood, gastrointestinal tract and other multi-system manifestations
.
In addition, the cardiotoxicity of hydroxychloroquine has also attracted much attention
.

Figure 1: Screenshot
of the study The latest study shows that the use of hydroxychloroquine is not associated with the development of long Q-T interval syndrome (LQTS) in patients with RA, after which the risk increases, and after 5 years of use, this risk becomes significant
.

However, it is worth mentioning that the absolute risk of developing LQTS over a 5-year period is very low, and the absolute risk difference is also lower
than that of other anti-rheumatic drugs (DMARD) to improve the condition.
And as follow-up time increased, both risks were found to be reduced, demonstrating the safety of long-term use of hydroxychloroquine in patients with RA[1].









How much is known about the cardiotoxicity of hydroxychloroquine?
For a long time, people's attitude towards hydroxychloroquine has been "love and hate"
.
Its cardiotoxicity is indeed a major reason why it is "feared", and it is currently believed that the cardiotoxicity of hydroxychloroquine is related to its accumulation in cells on ion channels and receptors and inhibition of autophagy, and its cardiotoxicity is premised on long-term and high-dose use [2].


Studies have shown that the changes in heart rhythm caused by hydroxychloroquine are reversible after discontinuation of the drug for a certain period of time, but because cardiomyopathy usually occurs after several months of treatment, it is almost irreversible and generally manifests as dose-dependent
.

▌ Cardiac electrophysiology and mechanical-related side effects have shown that sinus subrhythmic bradycardia[3] and atrioventricular and intraventricular conduction abnormalities[4] are more common in patients with RA and SLE using hydroxychloroquine[3] and conduction disorders are the most common side effects
[5].

It must be noted that the arrhythmias of these patients do not fully distinguish between pharmacogenic or pathogenic nature
.

It has also been found that no difference was found in the prevalence of ventricular block in patients treated with hydroxychloroquine compared with the prevalence of patients not taking hydroxychloroquine [6
].
In addition, hydroxychloroquine has been found to prolong the J-T interval, leading to dose-dependent lengthening of the Q-T interval margin [7].



Figure 2: The J-T interval is commonly used to assess the effect of drugs on cardiac repolarization, although studies have shown that hydroxychloroquine < 15 mg/kg·day (especially orally) does not cause a prolongation of the Q-T interval or only the Q-T margin [8-9], there have been cases of<b137> significant prolongation of the Q-T interval after 4 months with hydroxychloroquine at low doses (2-4 mg/kg·day) [10].
]
。
▌Myocardial side reactions At present, the effect of hydroxychloroquine on cardiac contraction is not clear, some non-mammalian experiments believe that hydroxychloroquine has a positive inotropic effect, which may be related to its activation of the sympathetic nerve center of the brain [11-12], while mammalian experiments
believe that there is no degeneration effect or negative inotropic effect [13-15], and there are
。
▌ Side effects
associated with myocardial remodeling and structural changes have shown that long-term use of hydroxychloroquine can lead to cardiomyopathy characterized by wall thickening and microstructural changes [16] with functional changes, including atrioventricular block, bundle branch block, mechanical dysfunction, diffuse hypokinesia, and decreased ejection fraction [17,4].

。 After myocardial infarction, the electrical changes caused by changes in the remodeling of the myocardium due to functional changes and other protein expression changes are called electrical restructuring (affecting the action potential and conduction, excitement-contraction coupling and contraction characteristics in the heart tissue), electrical restructuring is the cause of the increased probability of arrhythmia, hydroxychloroquine may also affect the electrical reconstruction
.








Is the heart really "injured" after long-term use of hydroxychloroquine?

One U.
S.
study included 8852 veterans (mean age 64±12 years, 14% female, 28% African-American), 4426 of whom initially took hydroxychloroquine, while another 4426 subjects initially used DMARDs
from other non-biological agents.
After 19 years of study follow-up, the study found that:

• The incidence of LQTS in the first 2 years was 0.
09% (4 cases) and 0.
11% (5 cases) in the hydroxychloroquine group and other DMARD groups, respectively;
•The 5-year incidence of LQTS was 0.
38% (17 cases) and 0.
14% (6 cases), respectively, and the relative risk in the hydroxychloroquine group increased significantly by 181%;
• In years 6-10, only 5 new cases of LQTS were added in the hydroxychloroquine group;
• The overall 10-year risk of LQTS remained significant (risk ratio 2.
17);
• In years 11-19, 1 new case of LQTS
was added to the hydroxychloroquine group.


Figure 3: The X-axis is the follow-up time, where: A is the incidence of the long Q-T interval (p=0.
04); B is the hospitalization rate for arrhythmias (p=0.
75); The C is all-cause mortality (p=0.
81)
study concluded that long-term use of hydroxychloroquine in patients with RA was not associated with hospitalization or all-cause mortality associated with arrhythmias, and although the incidence of LQTS with hydroxychloroquine was higher after 2 years and the risk was significant after 5 years of use, the absolute risk of developing LQTS at 5 years was very low and the absolute risk difference was lower
than that of other DMARDs.
And as follow-up time increased, both risks were found to be reduced, demonstrating the safety of long-term use of hydroxychloroquine in patients with RA
.








How can patients with RA regulate the use of hydroxychloroquine?
The European Union Against Rheumatism (EULAR) issued a 2016 opinion that hydroxychloroquine alone or in combination with other agents in Chinese patients with mild RA is still feasible [18], while the American Society of Rheumatology (ACR) latest 2021 recommendation to prioritize hydroxychloroquine for patients with low disease activity RA who do not receive DMARD [19].

At present, the domestic hydroxychloroquine product drug label recommends oral administration:
adults (including the elderly) the first dose of 400mg per day, taken in divided doses, when the efficacy is not further improved, the dose can be reduced to 200mg maintenance, if the treatment response is weakened, the maintenance dose should be increased to 400mg per day, the minimum effective dose should be used, should not exceed 6.
5mg / kg / day (according to the standard body weight rather than the actual body weight) or 400mg / day, Even smaller amounts
.

Children should use the minimum effective dose, should not exceed 6.
5 mg / kg / day (calculated according to the standard body weight) or 400 mg / day, or even less, children under the age of 6 are contraindicated, 200 mg tablets are not suitable for children
weighing less than 35 kg.

Each medication should be accompanied by eating or drinking milk
.
Hydroxychloroquine has a cumulative effect and takes several weeks to exert its beneficial effects, while minor adverse reactions may occur relatively early, if there is no improvement in treatment of rheumatic diseases for 6 months, treatment should be discontinued, in the treatment of light-sensitive diseases, treatment should be given
only when exposed to sunlight conditions to the greatest extent 。 For patients with RA in pregnancy, EULAR tends to use hydroxychloroquine throughout pregnancy [18], while ACR cites data from the research organization Mother To Baby in 2021 that the use of hydroxychloroquine in early pregnancy increases the risk of teratogenicity in the baby, but the maternal benefit outweighs the risk
.

Figure 3.
List of other adverse reactions of hydroxychloroquine [20]
Summary:
In China, hydroxychloroquine is still a key drug in the treatment of RA, so rational use of drugs is particularly important and should be cautious
.
The cardiac effects of hydroxychloroquine are not in a nutshell, and the so-called cardiotoxicity of patients with RA using hydroxychloroquine should also fully consider coexisting non-cardiac diseases (such as electrolyte disorders) or cardiac diseases (such as myocarditis).


In addition, although the new study confirms that the cardiac side effects of hydroxychloroquine are not as terrible as they are rumored, the combination of drugs that increase the burden on the heart should be avoided when used, such as the combination of macrolide antibiotics and hydroxychloroquine that can lead to prolongation of the Q-T interval, and the combination of 2 drugs with weak cardiotoxicity alone may exacerbate the effect on
the Q-T interval.

Finally, patients with RA should avoid long-term, high-dose hydroxychloroquine
.

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Hydroxychloroquine and Risk of Long QT Syndrome in Rheumatoid Arthritis:A Veterans Cohort Study with 19‐Year Follow‐up[J].
Arthritis Care&Research,2022.
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Cardiac effects and toxicity of chloroquine:a short update[J].
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Hydroxychloroquine-induced cardiotoxicity in a 39-year-old woman with systemic lupus erythematosus and systolic dysfunction[J].
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e1-981.
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Cardiac complications attributed to chloroquine and hydroxychloroquine:a systematic review of the literature[J].
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[6] Costedoat-Chalumeau N,Hulot J S,Amoura Z,et al.
Heart conduction disorders related to antimalarials toxicity:an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases[J].
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[10] Silva J A,Silva M B,Skare T L.
Chloroquine and QTc interval[J].
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[11] Chinyanga H M,Fletcher J J,Vartanian G A.
Increase of electrocardiogram voltage and contractile force of the frog's heart induced by chloroquine[J].
West African Journal of Pharmacology and Drug Research,1976,3(2):90-101.
[12] Marshall R J,Ojewole J A O.
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High‐dose chloroquine is metabolically cardiotoxic by inducing lysosomes and mitochondria dysfunction in a rat model of pressure overload hypertrophy[J].
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[15] Riou B,Barriot P,Rimailho A,et al.
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[16] Tönnesmann E,Kandolf R,Lewalter T.
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[17] Baguet J P,Tremel F,Fabre M.
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[20] Hydroxychloroquine sulfate tablets drug instructions







for more rheumatic drug knowledge where to look? Come to the "doctor's 👇
station" to take a look at the source of this article: Medical Rheumatic Immunization Channel This article author: Guizhi This article review: Chen Xinpeng Deputy Chief Physician Responsible Editor: Tangerine

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