Abstract
Background/objectives
Factors associated with chronic heart failure (CHF) in patients with systemic lupus erythematosus (SLE) have received little attention. Recent data on the use of hydroxychloroquine in the treatment of SARS-CoV-2 infection have cast doubt on its cardiac safety. The factors associated with CHF, including therapy with antimalarials, were analyzed in a large multicenter SLE cohort.
Methods
Cross-sectional study including all patients with SLE (ACR-1997 criteria) included in the Spanish Society of Rheumatology Lupus Register (RELESSER), based on historically gathered data. Patients with CHF prior to diagnosis of SLE were excluded. A multivariable analysis exploring factors associated with CHF was conducted.
Results
The study population comprised 117 patients with SLE (ACR-97 criteria) and CHF and 3,506 SLE controls. Ninety percent were women. Patients with CHF were older and presented greater SLE severity, organ damage, and mortality than those without CHF. The multivariable model revealed the factors associated with CHF to be ischemic heart disease (7.96 [4.01–15.48], p < 0.0001), cardiac arrhythmia (7.38 [4.00–13.42], p < 0.0001), pulmonary hypertension (3.71 [1.84–7.25], p < 0.0002), valvulopathy (6.33 [3.41–11.62], p < 0.0001), non-cardiovascular damage (1.29 [1.16–1.44], p < 0.000) and calcium/vitamin D treatment (5.29 [2.07–16.86], p = 0.0015). Female sex (0.46 [0.25–0.88], p = 0.0147) and antimalarials (0.28 [0.17–0.45], p < 0.000) proved to be protective factors.
Conclusions
Patients with SLE and CHF experience more severe SLE. Treatment with antimalarials appears to confer a cardioprotective effect.
Keywords: Systemic lupus erythematosus, Chronic heart failure, Antimalarials
Introduction
Cardiovascular disease (CVD) is a main cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE) [1,2]. The 2020 meta-analysis by Yazdany et al. [3] showed SLE to be associated with an increased risk of myocardial infarction (pooled relative risk, 2.99 [95% CI 2.34–3.82]). However, the prevalence and factors associated with congestive heart failure (CHF) in SLE patients have not been studied in sufficient depth [4,5].
Antimalarials are associated with a reduced risk of CVD in the vast majority of published observational studies [6], [7], [8]. However, data collected during the COVID-19 pandemic, including those reported in a randomized controlled trial (REMAP-CAP), suggest that hydroxychloroquine might carry a risk of cardiotoxicity, at least when used for treating SARS-CoV-2 infection [9], [10], [11]. Other studies, such as the RECOVERY trial, did not confirm cardiotoxicity in the setting of COVID-19 [12]. Reported cases of cardiotoxicity induced by antimalarials have consisted mainly of arrhythmias related to QTc interval prolongation, particularly when combined with other drugs and administered at higher doses than usual. However, concerns still remain regarding the cardiac safety of antimalarials prescribed for the usual indications. Additionally, several studies demonstrated that chronic exposure to antimalarials can induce, albeit rarely, so-called antimalarial-induced cardiomyopathy [13].
Due to the current lack of safety data from randomized controlled trials investigating long-term treatment with antimalarials for rheumatic diseases, large observational studies can serve as a crucial means of confirming the absence of cardiac events associated with hydroxychloroquine and other antimalarial drugs. Using the data recorded in a large multicenter SLE cohort drawn from the RELESSER register, we carried out an analysis not only to identify factors associated with CHF in patients with SLE, but also to gain insight into the cardiac safety of long-term therapy with hydroxychloroquine in this population.
Methods
All patients registered in the retrospective phase of the RELESSER register (RELESSER-TRANS) who met at least 4 of the 1997 criteria of the American College of Rheumatology (ACR) were considered for this study. The methodology, including definitions of variables and the main characteristics of the register, has been described elsewhere [14]. Patients with or without CHF were compared in terms of cumulative clinical characteristics, treatment at any time, severity of SLE (as estimated using the Katz index) [15], organ damage (modified Systemic Lupus International Collaborating Clinics [SLICC]/ACR Damage Index, i.e., excluding cardiovascular components [mSDI]), classic cardiovascular risk factors, and comorbidity (Charlson index). In contrast, activity was measured only at the last visit (SELENA-Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]).
CHF was defined according to standard clinical and imaging criteria, as recorded in the clinical charts.
Dichotomous variables were compared using the Fisher exact test; numerical variables were compared using the Mann-Whitney test, since none of them fulfilled the assumption of normality.
A multivariable analysis was carried out to identify variables associated with CHF. A total of 35 variables, all of which were significant in the bivariate analysis, were ultimately included in the multivariable analysis. Up to 21 variables were automatically deleted and, while the remaining selection was used to build the model manually, an analysis of variance test was used to compare nested models. Multicollinearity was tested using the generalized variance inflation factor (GVIF) method [16].
Statistical significance was set at p < 0.05. All the analyses were carried out using R version 4.0.2.
Results
CHF was detected in 152 of the 3658 patients enrolled in the RELESSER registry. We excluded 17 patients whose diagnosis of CHF was made before that of SLE and an additional 18 patients whose medical records contained no reliable information regarding the date of onset of CHF. Finally, 117 patients (3% of the whole cohort) with SLE and CHF were included in the analysis. The mean age of patients with CHF at their last visit was higher than in controls without CHF (59.8 ± 18.2 vs. 46.2 ± 4.3 years), 90% were females and 93% were Caucasian).
Onset of CHF took place a median (IQR) of 9.4 years (4.2–18.3) following the diagnosis of SLE.
The results of the bivariate analysis, in which the eventual association with CHF was tested, are provided in Tables 1 and 2 . In order to clarify the presentation of data, we segregated the potential confounding variables, i.e., those that are known to be associated with CHF in the general population (Table 2). Briefly, patients with CHF had more severe disease (Katz index, median [IQR], 4 [3–5] vs 2 [1–3]), organ damage (mSDI: 3 [2–4] vs 0 [0–1]), and greater degree of comorbidity (as measured using a modified Charlson index, excluding cardiovascular items, 4 [3–6] vs 1[1–3]). In addition, more patients with CHF died from cardiovascular causes (37.5% vs 6.7%) or any other cause (43.2% vs 4.7%) (p < 0.0001 for all comparisons). Likewise, patients with CHF were more often refractory to standard treatments (33.3% vs 24%, p = 0.0377) and were more frequently hospitalized for SLE-related causes (median 3 [1–5] vs 1 [0–2], p < 0.0001). The results of the multivariable analysis are shown in Table 3 . GVIF values were less than 1.5 for all of the independent variables included in the model, thereby excluding collinearity.
Table 1.
Bivariate analysis of factors associated with chronic heart failure (CHF) (lupus-related characteristics).
| Cumulative clinical characteristics and treatments | Entire cohort N/total*(%)⁎⁎ | Patients without CHF N/total*(%)⁎⁎ | Patients with CHF N/total*(%)⁎⁎ | p-value |
|---|---|---|---|---|
| Cutaneous manifestations | 2,622/3623 (72.4) | 2,540/3454 (73.5) | 82/117 (70.1) | 0.3963 |
| Constitutional symptoms | 687/3623 (19.0) | 638/3425 (18.6) | 49/116 (42.2) | <0.0001 |
| Myositis | 131/3509 (3.7) | 124/3395 (3.7) | 7/114 (6.1) | 0.1994 |
| Articular manifestations | 2,760/3533 (78.1) | 2,671/3416 (78.2) | 89/117 (76.1) | 0.5707 |
| Pulmonary manifestations | 223/3623 (6.2) | 201/3455 (5.8) | 22/117 (18.8) | <0.0001 |
| Neuropsychiatric lupus | 454/3623 (12.5) | 414/3441 (12.0) | 40/117 (34.2) | <0.0001 |
| Glomerulonephritis | 690/3623 (19.0) | 655/3506 (18.7) | 35/117 (29.9) | 0.0038 |
| Chronic kidney failure | 186/3488 (5.3) | 150/3372 (4.4) | 36/116 (31.0) | <0.0001 |
| Antiphospholipid syndrome | 490/3546 (13.8) | 460/3429 (13.4) | 30/117 (25.6) | 0.0005 |
| Small vessel thrombosis | 128/3481 (3.7) | 112/3364 (3.3) | 16/117 (13.7) | <0.0001 |
| Vasculitis | 317/3494 (9.1) | 296/3379 (8.8) | 21/115 (18.3) | 0.0014 |
| Raynaud syndrome | 1167/3460 (33.7) | 1122/3346 (33.5) | 45/114 (39.5) | 0.1913 |
| Statins, any time | 819/3257 (25.1) | 746/3141 (23.8) | 73/116 (62.9) | <0.0001 |
| Calcium or vitamin D, any time | 2,217/3293 (67.3) | 2107/3177 (66.3) | 110/116 (94.8) | <0.0001 |
| Corticosteroids, any time | 3,034/3410 (89.0) | 2,920/3293 (88.7) | 114/117 (97.4) | 0.0013 |
| Cyclophosphamide, any time | 761/3384 (22.5) | 723/3268 (22.1) | 38/116 (32.8) | 0.0091 |
| Mycophenolate, any time | 563/3323 (16.9) | 540/3207 (16.8) | 23/116 (19.8) | 0.3796 |
| Antimalarials, any time | 2,830/3395 (83.4) | 2768/3278 (84.4) | 62/117 (53) | <0.0001 |
| Time on antimalarials (months), mean (SD) | 78.16 (78.4) | 78.28 (78.6) | 73.87 (70.9) | 0.5199 |
| Creatinine, mean (SD) | 0.92 (1.16) | 0.90 (1.14) | 1.50 (1.33) | <0.0001 |
| Anti-Ro antibodies | 1,371/3473 (39.5) | 1,326/3360 (39.5) | 45/113 (39.8) | 1 |
| Anti-RNP antibodies | 869/3455 (25.2) | 837/3341 (25.1) | 32/114 (28.1) | 0.4446 |
| Low complement | 2,734/3510 (77.9) | 2,632/3395 (77.5) | 102/115 (88.7) | 0.0040 |
| Antiphospholipid antibodies | 1,343/3623 (37.1) | 1,292/3506 (36.9) | 51/117 (43.6) | 0.1449 |
| Katz SI#, median (IQR) | 2 [1–3] | 2 [1–3] | 5 [3–5] | < 0.0001 |
| mSDI§, median (IQR) | 0 (0–1) | 0 (0–1) | 3 [2–4] | < 0.0001 |
“total” means number of patients with the value available.
unless otherwise specified.
Katz SI = Katz severity index.
mSDI = modified SLICC/ACR damage index (i.e., without cardiovascular items).
Table 2.
Bivariate analysis of factors associated with chronic heart failure (CHF) (confounding variables, i.e. variables commonly associated to CHF in general population).
| Total N/total*(%)⁎⁎ | Patients without CHF N/total*(%)⁎⁎ | Patients with CHF N/total*(%)⁎⁎ | p-value | |
|---|---|---|---|---|
| Age at inclusion, mean (SD) | 46.64 (14.71) | 46.19 (14.36) | 59.78 (18.24) | <0.0001 |
| Hypertension | 1031/3564 (28.9) | 945/3447 (27.4) | 86/117 (73.5) | <0.0001 |
| Alcoholism | 134/3283 (4.1) | 126/3172 [4] | 8/111 (7.2) | 0.1345 |
| Diabetes | 171/3539 (4.8) | 154/3424 (4.5) | 17/115 (14.8) | <0.0001 |
| Hyperlipidemia | 1073/3451 (31.1) | 999/3335 (30) | 74/116 (63.8) | <0.0001 |
| Ischemic heart disease | 116/3570 (3.2) | 88/3454 (2.5) | 28/116 (24.1) | <0.0001 |
| Myocarditis | 23/3515 (0.7) | 11/3398 (0.3) | 12/117 (10.3) | <0.0001 |
| Cardiac arrhythmia | 139/3548 (3.9) | 101/3432 (2.9) | 38/116 (32.8) | <0.0001 |
| Pulmonary embolism | 119/3554 (3.3) | 108/3437 (3.1) | 11/117 (9.4) | 0.0016 |
| Pulmonary hypertension | 104/3334 (3.1) | 73/3218 (2.3) | 31/116 (26.7) | <0.0001 |
| Cardiac valvulopathy | 114/3375 (3.4) | 76/3260 (2.3) | 38/115 (33) | <0.0001 |
“total” means number of patients with the value available ⁎⁎ unless otherwise specified.
Table 3.
Factors associated with congestive heart failure (multivariable analysis).
| Odds Ratio | 95% CI | p-value | |
|---|---|---|---|
| Calcium or vitamin D | 5.29 | 2.07 - 16.86 | 0.0015 |
| Antimalarials any time | 0.28 | 0.17 - 0.45 | <0.0001 |
| Sex (female) | 0.46 | 0.25 - 0.88 | 0.0147 |
| Ischemic heart disease | 7.96 | 4.01 - 15.48 | <0.0001 |
| Cardiac arrhythmia | 7.38 | 4.00 - 13.42 | <0.0001 |
| Pulmonary hypertension | 3.71 | 1.84 - 7.25 | 0.0002 |
| Cardiac valvulopathy | 6.33 | 3.41 - 11.62 | <0.0001 |
| Hospitalization (due to SLE) | 3.74 | 1.81 - 8.65 | 0.0008 |
| mSDI * | 1.29 | 1.16 - 1.44 | <0.0001 |
mSDI = modified SLICC/ACR damage index (i.e., excluding cardiovascular items).
Discussion
Despite the well-established high prevalence of CVD in SLE patients, little attention has been paid to risk factors associated with CHF. In this study, using historically gathered data, we identified factors associated with CHF in a large multicenter and well-characterized, European lupus cohort. Consistent with findings reported elsewhere, the usual causes of CHF in the general population were all associated with CHF in SLE, namely, ischemic heart disease, arrhythmia, pulmonary hypertension, and valvulopathy. These cardiovascular conditions exhibit the strongest association with CHF in terms of the odds ratio. Additionally, patients with CHF had greater cumulative non-cardiovascular organ damage, were more frequently hospitalized owing to SLE, and died more often from both cardiovascular and non-cardiovascular causes, suggesting that they constitute a subset with more severe disease.
Notably, antimalarials conferred some cardio-protective effects in our analysis. These drugs are considered essential medications for treatment of SLE [17], [18], [19], [20]. Although hydroxychloroquine and chloroquine are generally well-tolerated, they can have severe cardiologic adverse effects, including cardiomyopathy and conduction defects [13]. Furthermore, a recent survey from the United States Food and Drug Administration Adverse Event Reporting System indicated a relatively high risk of cardiomyopathy and myocardial disorders following exposure to hydroxychloroquine in older adults [21]. In contrast, the use of antimalarials was associated with a lower prevalence of CHF in our large multicenter retrospective SLE cohort, and, interestingly, this effect occurred independently of disease severity. Of note, this apparently cardioprotective effect was also documented independently of ischemic heart disease, suggesting that mechanisms other than antithrombotic effects could be involved, for example, better control of subclinical myocarditis or overall disease activity.
The protective effect of female sex is not surprising, given the well-known lower frequency of CHF among women in the general population [22].
An association between CHF and the use of calcium or vitamin D was found and confirmed in the multivariable analysis. A possible association between 25-hydroxyvitamin D and CVD in patients with SLE was previously suggested based on data from a large international inception cohort [23]. While the variable used in this study is not a direct measure of vitamin D status in the study patients, our results indicate that phosphate and calcium metabolism may have an impact on CVD in persons with SLE. One explanation for the positive association between CHF and vitamin D or calcium would be an underlying deficiency, probably related to corticosteroid treatment, which could necessitate supplements. Thus, we can hypothesize that vitamin D has a cardioprotective effect, consistent with findings for the general population [24,25]. However, a recent meta-analysis of studies carried out in the general population suggests that vitamin D supplementation does not confer cardiovascular protection [26]. Obviously, prospective and specifically designed studies would be required to test such a hypothesis in SLE.
Our study is subject to a series of limitations. First, as it is not population-based, the prevalence of CHF may be underestimated. In particular, one must take into account the fact that several patients with CHF were finally excluded, since we were unable to determine the time of onset of CHF. Moreover, bias inherent to the study's retrospective design, particularly under-reporting of explanatory or confounding variables, cannot be excluded. Given the cross-sectional nature of our study, it is not possible to talk about protective or deleterious factors; the variables found to be significant in the multivariable analysis are merely associations. Regarding the dependent variable, given that CHF is a highly relevant clinical event and easily diagnosed in daily clinical practice, it seems unlikely that it would go unnoticed and not be recorded. However, we cannot exclude underdiagnosis of ventricular disfunction. On the other hand, assessment of exposure to antimalarials was not robust, as it was based on a single categorial variable, namely the use of antimalarials at any time. On the other hand, the large number of patients included could minimize the impact of this definition-related limitation.
Conclusions
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Patients with SLE and CHF experience more severe SLE, with more pronounced cumulative damage.
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Treatment with antimalarials seems to confer some cardioprotective effects.
Key messages
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CHF is a late complication of SLE and is associated with high mortality.
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Patients with SLE and CHF experience more severe SLE, with more pronounced cumulative damage, higher overall SLE-related mortality, and greater refractoriness to SLE treatments.
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Treatment with antimalarials, as usually administered in patients with SLE, is not only safe for the heart, but might confer cardioprotective effects.
Declaration of Competing Interest
All authors declare that they have no conflicts of interest associated with this original article.
Acknowledgments
Ethical approval
The RELESSER register and studies derived therefrom have been approved by the Ethics Committee of Doctor Negrin Hospital (ID: RELES-SER-2009–01). All patients gave their informed consent for their data to be used in the study.
Funding statement
This work was supported by the Spanish Foundation of Rheumatology.
Acknowledgements
We are grateful to the entire group of RELESSER registry researchers. We also thank the Spanish Society of Rheumatology for support in the revision of the English translation.
Data availability statement
Data are available at the Spanish Society of Rheumatology Research Unit under request, wherever legally and ethically possible.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available at the Spanish Society of Rheumatology Research Unit under request, wherever legally and ethically possible.