Hydroxychloroquine use is not associated with QTc length in a large cohort of SLE and RA patients

Hydroxychloroquine (HCQ) has long been a cornerstone therapy for systemic lupus erythematosus (SLE) and is commonly used as monotherapy or combined with other disease modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). HCQ neutralizes acidic cytoplasmic components within the lysosome, leading to downstream alterations in antigen processing and inhibition of toll-like receptors [1, 2]. The observed cutaneous, retinal, and musculoskeletal toxicities are thought to arise from long-term storage of its metabolite, 4-aminoquinolone, in these tissues [2].

Acute cardiovascular (CV) toxicities from short-term exposure of HCQ (and subsequent blocking of potassium channels within myocytes) manifest as QT interval prolongation, and when combined with additional baseline risk factors, such as age, sex, high levels of anti-Ro antibodies [3], and arrhythmogenic congenital long QT syndromes [4], acute arrhythmic events (i.e., torsades de pointes) also occur [5]. With long-term exposure, HCQ metabolites may also accumulate in the myocardium and result in a cardiomyopathy with concentric hypertrophy and conduction abnormalities [1, 5, 6]. In fact, 33 of 42 histologically confirmed cases of HCQ induced cardiomyopathy originated from RA and SLE patients, who on average had been on treatment for 13 years [1]. Moreover, 14 of those 42 cases progressed to third-degree atrioventricular block. However, there are no current guideline-based recommendations for CV screening in the setting of prolonged HCQ use.

Recent reports [7, 8] of possible associations between concurrent HCQ and azithromycin use and QTc prolongation in those receiving treatment for coronavirus disease 2019 (COVID-19)-associated pneumonia have raised further concerns for HCQ-associated cardiotoxicity. However, the wide spectrum of cardiotoxic effects of COVID-19 itself (arrhythmias, myocarditis, microvascular injury, stress cardiomyopathy) [9] confound these observations. In observational (mostly retrospective) studies in rheumatic disease patients [10‐14], there were no differences in QTc prolongation in HCQ users vs non-users, nor was there an association between QTc length and HCQ use, keeping in mind that these studies did not consistently account for the use of other prolonging QTc medications. We therefore investigated associations between HCQ use and QTc length in an SLE and RA cohort without known CV disease (CVD), accounting for the use of various QTc prolonging medications.

In this large cohort of RA and SLE patients, HCQ use was not associated with QTc length when adjusted for potential confounders such as age and other medications affecting QTc length. The adjusted QTc length was comparable between HCQ users and non-users (438 ms vs 437 ms). Although up to 44% of the combined cohort had a QTc ≥ 440 ms, HCQ use was not a predictor of prolonged QTc.

QTc length as an outcome remains of paramount interest, since in the general population and in selected subpopulations (i.e., the elderly, patients with coronary artery disease, and the critically ill), prolonged QTc length (defined in those studies as > 450 ms in men and > 470 ms in women) independently predicts sudden cardiac death [19, 20]. In fact, even moderate QTc prolongation between 420 and 440 ms has been associated with all-cause mortality [21]. In a retrospective cohort study of RA patients, idiopathic QTc prolongation [22] was associated with an almost 30% increase in all-cause mortality (HR 1.28; 95% CI 0.91–1.81, p = 0.16). Furthermore, in a prospective cohort of RA patients, a 50-ms increase in QTc interval was independently associated with a twofold risk of mortality (HR =2.18, 95% CI 1.09, 4.35), and CRP levels were also independently associated with QTc length [10]. In our study, prednisone use was associated with a lower QTc length in the combined RA + SLE cohort, in addition to being a negative predictor of QTc≥440 ms. From this observation, we hypothesize that reduction of systemic inflammation mitigated any deleterious effects on the conduction system and thus decreased the risk of QTc prolongation. However, when we examined these associations separately by individual cohorts, in the SLE cohort, CRP > 10 mg/L and not prednisone use was associated with (higher) QTc length. Given that 79% of our SLE cohort demonstrated CRP > 10 mg/L, despite 93% using prednisone, we postulate that in this group, high disease activity (and thus inflammatory) burden, unmitigated by prednisone use, increased the risk of QTc prolongation. The specific interplay between inflammation and arrhythmogenic potential, as well as mechanisms leading to arrhythmia, merits further exploration.

HCQ-associated QTc prolongation and subsequent arrhythmia development received considerable attention during its widespread use in COVID-19 patients. In an uncontrolled study of COVID-19 patients receiving HCQ alone or HCQ and azithromycin for associated pneumonia [8], baseline to treatment change in QTc was higher in the HCQ + azithromycin group vs HCQ alone. It is also worthwhile noting that in the prior study, up to 19% of those receiving HCQ alone had a QTc > 500 ms (and 21% in combination group) and 8% had a clinically significant increase > 60 ms, with one episode of torsades de pointes reported. However, independent effects of COVID-19 infection on the cardiac conduction system [9] and indication bias (severe COVID-19 patients more likely to receive HCQ) must be considered in interpretation of these data. Similarly, Ramireddy et al. [23] reported a significantly higher change in QTc from baseline to treatment in the HCQ and azithromycin group vs HCQ alone (17 ± 39 ms vs 0.5 ± 40 ms; p = 0.07). More concerning, up to 12% of total patients in this study (receiving HCQ alone, azithromycin alone, or both) had critical QTc prolongation (defined as maximum QTc ≥ 500 ms (if QRS < 120 ms) or QTc ≥ 550 ms (if QRS ≥120 ms) and QTc increase of ≥ 60 ms); however, no torsades de pointes was documented. The results of a more recent randomized controlled trial [24] were more reassuring in that, in 1561 COVID patients randomized to the HCQ arm and loaded with high doses of HCQ (800 mg × 2 doses followed by 400 mg every 12 h for 9 days or until discharge), there were no significant differences in terms of frequency of arrhythmias compared to the usual care group.

As for rheumatologic patients, SLE patients treated with high cumulative doses (700–1300 g) of antimalarials from several months to decades demonstrated bundle branch block and third-degree AV block (with some leading to Torsades de Pointes) [25‐28]. However, interpretation from these case reports is limited due to absence of controls. It is also important to note that current trends in HCQ dosing have become more conservative due to heightened awareness of retinal toxicity. More recently, Lane et al. [29] reported no increased risk of cardiac arrhythmias (calibrated HR 0.90; 95% CI 0.78–1.03; p < 0.01) in HCQ users (400 mg/day for 30 days) vs sulfasalazine users in a retrospective review of 14 multinational databases of RA patients. Liu et al. [30] reported a lower risk of CV disease including sudden cardiac arrest/death in HCQ/chloroquine (CQ) users vs non-users (RR 0.72; 95% CI 0.56–0.94; p = 0.013) in a meta-analysis of various rheumatologic patients. Various cardioprotective (thromboprotective and cholesterol reducing) effects of HCQ/CQ [31, 32] may partially explain this finding but the absence of clinical trial data and CV/metabolic parameters limit interpretation. In another prospective study [33] of RA patients, incidence of long QT syndrome or arrhythmia-related hospitalizations were comparable between HCQ use vs non-HCQ disease-modifying anti-rheumatic drug (DMARD) use.

Specifically, the lack of association of HCQ use with overall QTc length in our results is consistent with prior publications in RA and SLE patients [10‐13, 22]. The main strength of our study is its sample size as it represents one of the largest multiethnic studies inclusive of both SLE and RA patients. Importantly, we accounted for the concurrent use of a wide variety of QTc prolonging or arrhythmogenic medications, which was not consistently done in previous literature. Although SLE data were obtained retrospectively via ICD 9/10 codes on EMR review, we restricted analyses to SLE patients who demonstrated consistent care at our institution (≥ 2 visits). For both the SLE and RA cohorts, QTc length was calculated by standardized Bazett’s formula and confirmed by a blinded, trained cardiac electrophysiologist (PP). The main limitations of our study include the lack of data on HCQ adherence (i.e., via patient report, and/or metabolite levels), as well as cumulative dosage or length of therapy, as it is known that HCQ adherence in the SLE population is variably poor and the risk of HCQ toxicity increases with cumulative dosage. Moreover, although we detected a statistically significant interaction between antipsychotics and HCQ use, we acknowledge the small number of observations (< 20 who reported on both antipsychotic and HCQ use) that may preclude interaction testing as well as produce an overestimation of interaction effect. In addition, we did not obtain or analyze pre-HCQ ECGs (determined only at the time of HCQ use for both SLE and RA cohorts) and therefore cannot make conclusions about pre- and post-exposure change in QTc length. Finally, because we excluded patients with clinical CVD who received ECG screening, our findings may not directly apply to those patients, who may have other risk factors associated with prolonged QTc. Given the prevalence of associated CV risk factors (hypertension, diabetes), we surmise that our patients likely had some underlying, subclinical CVD.

In a combined large multiethnic cohort of RA and SLE patients, QTc length did not significantly differ in HCQ users compared with non-HCQ users, nor was it associated with a QTc ≥ 440 ms, even while adjusting for potential confounders. There was a notable statistical interaction between the use of HCQ and use of antipsychotics in the combined RA and SLE cohort. Our data suggests that HCQ does not increase the arrhythmogenic risk for patients with rheumatologic conditions.