Increased risk of cardiovascular disease in patients with cutaneous lupus erythematosus

Cutaneous lupus erythematosus (CLE) can occur both independently or as part of systemic lupus erythematosus (SLE), it can manifest as localized or generalized cutaneous lesions as well as extracutaneously.

As part of these extracutaneous manifestations, the condition may be associated with an increased risk of adverse cardiovascular problems including thromboembolism, systemic inflammation, heart failure (HF), and cardiac arrhythmias. While mechanisms have been postulated for this increased risk, research has been sparse and limited to small study populations. Below, we summarize results from a large, nationwide cohort study by Shams‑Eldin, et al.,¹ published in Clinical Rheumatology in July 2022, exploring adverse cardiac outcomes in patients with CLE relative to the control population.

Study design¹

In this case-controlled observational cohort study, patient searches were performed in three Danish national registries between 1996 and 2018 according to the International Classification of Diseases 10th Revision (ICD-10), for all patients aged 18 or over. The primary outcome was heart failure incidence. Secondary outcomes included

• hospitalization with heart failure (primary and secondary inpatient diagnosis);
• atrial fibrillation or flutter;
• implantable cardioverter-defibrillator after ventricular arrhythmias or cardiac arrest;
• pacemaker implantation after atrioventricular block (advanced second or third degree) or sinoatrial dysfunction;
• myocardial infarction;
• ischemic stroke;
• venous thromboembolism; 
• all-cause mortality.

The study design is outlined in Figure 1.

CLE, cutaneous lupus erythematosus; SLE, systemic lupus erythematosus.
*Adapted from Shams-Eldin, et al.^1
†Cardiovascular disease included heart failure, atrial fibrillation or flutter, ventricular arrhythmias (i.e., ventricular tachycardia, flutter, or fibrillation), cardiac arrest, atrioventricular block (advanced second or third degree), sinoatrial dysfunction, ischemic stroke or heart disease, an implantable cardioverter-defibrillator or pacemaker implantation, and venous thromboembolism (deep venous or pulmonary).
^‡Comorbidities included peripheral artery disease, diabetes, hyper- tension, chronic obstructive pulmonary disease, and chronic kidney disease.

Results

Overall, 2,062 patients with CLE were matched to 8,248 unaffected individuals. The median age of participants was 50 years old (interquartile range [IQR], 37–62 years) and 22.3% were men. Median follow-up was 6.3 years and 87.9% and 12.1% of patients were diagnosed with CLE in outpatient and impatient settings, respectively. Baseline characteristics can be seen in Table 1. The percentage of CLE diagnoses among patients included:

• discoid lupus erythematosus (67%)         
• subacute CLE (20.8%)
• other forms of CLE (12.3%)

Table 1. Baseline characteristics of patients and background population*

CLE, cutaneous lupus erythematosus; IQR, interquartile range; N/A, not applicable; RAS, renin angiotensin system. *Adapted from Shams-Eldin, et al.1
Characteristic, % (unless otherwise stated)	Background population (n = 8,248)	CLE population (n = 2,062)	p value
Median age (IQR), years	50 (37–62)	50 (37–62)	N/A
Men, %	22.3	22.3	N/A
Comorbidities
Hypertension	11.8	11.8	N/A
Peripheral artery disease	1.3	1.3	N/A
Diabetes	2.3	2.3	N/A
Malignancy	4.8	6.6	0.006
Chronic kidney disease	1.7	1.7	N/A
Chronic obstructive pulmonary                disease	2.6	2.6	N/A
Liver disease	1.2	3.1	<0.001
Medical treatment at baseline
Lipid-lowering medication	6.1	5.9	0.77
Aspirin	3.9	5.0	0.02
Beta-blockers	5.3	5.0	0.48
Calcium-channel blockers	6.2	7.3	0.06
RAS inhibitors	10.7	11.1	0.55

Patients with CLE were more likely to have a history of malignancy (6.6% vs 4.8%, p = 0.006) or liver disease (3.1% vs 1.2%, p < 0.001) than the background population, while 19.7% of patients with CLE went on to develop SLE (median time, 1.5 years; IQR, 0.3–4.5 years).

The 10-year cumulative incidence of adverse cardiac outcomes can be seen in Table 2. There was no gender difference within associations between CLE and adverse cardiovascular outcomes.

Table 2. 10-year cumulative incidence of adverse cardiac outcomes*

The risk of HF was significantly higher in patients with CLE (4.15 events/1,000 person years; 95% CI, 3.27–5.26) compared with the background population (2.72 events/1,000 person years; 95% CI, 2.39–3.10), with an adjusted hazard ratio of 1.67 (95% CI, 1.24–2.24).

Study strengths and limitations

This study included a large, nationwide data set from validated registries and did not actively select for patients, reducing the possibility of selection bias; there was also long-term follow up with no patient loss. However, as the study was limited to the Danish population who are primarily of white ethnicity and, as an observational study, was also limited to identifying associations and not causality, further large-scale studies examining the effect of race are needed to confirm the generalizability of these findings. Lastly, the authors reported a lack of available data on other factors affecting the cardiovascular system, such as body mass index and history of smoking.

Conclusion

This study featured well-matched case and control sets and shows that patients with CLE are at increased risk of long-term cardiovascular disease relative to unaffected individuals, with higher rates of HF, cardiac arrhythmias, and thromboembolism. This association is unaffected by gender. Greater clinical surveillance for cardiovascular complications and patient education may be beneficial to reduce associated morbidity and mortality. Further large clinical studies are needed in order to replicate the findings and validate them in other populations.