Discussion
The short-term and long-term survival of patients with SLE and LN have improved remarkably over the past few decades, owing to the advances in immunosuppressive and general medical treatments.78–81 With better early survival, CV morbidity and mortality have become a growing concern in the long-term management of patients with SLE and LN.1 82 Our meta-analysis results showed that the presence of LN in patients with SLE was associated with increased risk of various conventional CVD risk factors including HT, dyslipidaemia and DM, and also elevated odds of CV mortality. Our observations are clinically important because these CVD risk factors are potentially amenable to treatment and their adequate control can modulate the risk of CV morbidity and mortality.
In this meta-analysis, patients with SLE with LN showed a fivefold risk of developing HT compared with those without nephritis. The prevalence rates of HT were up to 80% among patients with SLE with LN, and the SBP and DBP were both significantly higher than patients with renal involvement. The kidneys are an important organ for blood pressure regulation, and hence HT is highly prevalent among patients with CKD and often an early indication of renal impairment.83–85 The increased propensity for HT in patients with LN can be explained by cumulative renal damage caused by previous severe nephritis or repeated renal flares. The high rates of HT in patients with LN call for more aggressive blood pressure control to reduce proteinuria and retard further deterioration of renal function. Our findings also suggested that patients with LN older than 40 years are particularly affected as age per se is an important risk factor for HT. Our subgroup analysis revealed that Latin American patients with LN had significantly higher risk of HT compared with other ethnicities. Indeed, Latin Americans are recognised to have more resistant HT compared with patients of other racial backgrounds.86 87
Our results showed that patients with SLE with LN were associated with significantly higher TC, LDL and risk of hyperlipidaemia compared with those without LN. One previous study from our group also reported high prevalence of dyslipidaemia (up to 60%) in patients with LN despite achieving disease quiescence.14 Dyslipidaemia in patients with LN can be contributed by concomitant immunosuppressive medications (eg, low-dose corticosteroids), low-grade proteinuria, chronic renal insufficiency and systemic inflammatory states.88–91 Our subgroup analysis further showed that patients with LN younger than 40 years appeared to be more affected. In general, younger patients tend to have lower risk of dyslipidaemia, and the presence of renal abnormalities such as proteinuria and renal impairment in patients with LN may predispose them to aberrant lipid profiles. While previous studies suggested that African Americans generally show more favourable lipid profiles compared with other ethnicities,88 92–94 our subgroup analysis indicated that the presence of LN may nullify such racial advantage.
Our present meta-analysis data revealed that patients with SLE with LN conferred almost a twofold risk of DM compared with those without LN. The increased propensity for DM is highly related to the use of corticosteroids for induction-maintenance treatment for LN, and indeed our subgroup analysis corroborated with this notion. While young individuals generally have low risk of DM, our data suggested that the presence of LN significantly elevates the odds of DM in young patients with SLE. The development of DM is clinically important because this not only increases the risk of macrovascular complications such as MI or CVA, but also the various microvascular complications including diabetic nephropathy, retinopathy and neuropathy.95–97 It remains unknown whether the growing use of calcineurin inhibitors (eg, tacrolimus or voclosporin) for the management of LN may further increase the risk of DM in patients with SLE.98 99 The escalated risk of DM and HT in patients with LN receiving corticosteroids calls for better attempts and strategies to minimise overall steroid exposure, especially in patients with stable disease.100
With increase in various conventional CV risk factors, one would expect a significantly higher risk and prevalence of CVD in patients with SLE with LN compared with those without LN. In this meta-analysis, the presence of LN in patients with SLE was associated with numerically higher prevalence and odds of MI and CVA compared with those without LN, though the results did not reach statistical significance. This may be related to the limited number of studies that have included both patients with SLE with LN and those without LN. While it appeared that the results were ‘numerically higher’ in the LN group, it could equally suggest that there was indeed no significant difference even if the sample size was increased. It also remains possible that SLE per se is a very strong risk factor for CVD, and that the impact of LN cannot be fully demonstrated. Of note, our proportional meta-analysis showed that the prevalence of MI was doubled in patients with LN compared with patients with SLE in general. Furthermore, our data also suggest that patients with SLE with LN have substantially higher CV mortality compared with those without LN. Indeed, CVD is a leading cause of death in patients with SLE, conferring a 13-fold risk of mortality compared with age-matched and gender-matched general population.3 Apart from having more traditional CV risk factors, the increased risk of CVD and CV mortality in patients with LN may be explained by endothelial dysfunction and increased prothrombotic tendency, as evidenced by elevated levels of endothelial cell function markers such as platelet endothelial cell adhesion molecules,101 vascular endothelial-cadherin, serum anti-endothelial cell autoantibodies,102 activated leucocyte cell adhesion molecule,101 103 VCAM-1, ICAM-1, syndecan-1, hyaluronan and thrombomodulin.103–107
There are a few key limitations to this meta-analysis. First, there are few studies with CVD data on both patients with LN and those without LN, making the assessment of the impact of LN on CVD in patients with SLE difficult. During the screening process, we found that many important and well-conducted studies (some with very large patient numbers) were excluded because they did not have clinical data for both arms. To address this problem, we conducted the proportional meta-analysis to supplement the results of two-arm meta-analysis, which calculates the weighted average of each arm separately and comparing them with statistical method. We have chosen to compare general patients with SLE with patients with LN, as there were not any studies that solely reported on patients with SLE without nephritis. The potential drawback was that the data in the SLE arm would be contaminated by patients with LN inside the SLE cohort. In addition, proportional meta-analysis is bound to have between-study bias as the baseline characteristics of the LN group and SLE group were not proven to be comparable. To circumvent these issues, we have interpreted the results of proportional meta-analysis with respect to the findings in two-arm meta-analysis, and the data/conclusions were largely concordant.
Furthermore, definitions of outcomes are often incomplete in the included studies, especially those in proportional meta-analysis. Other issues include that some studies may have defined HT by the use of anti-HT drugs, and yet patients with LN often receive ACE inhibitors/angiotensin receptor blockers for proteinuria reduction rather than treatment for HT. In addition, data on other major adverse cardiovascular events outcomes such as heart failure are also lacking. There is insufficient information to analyse the effect of immunosuppressive treatments and anti-malarials on CV risk factors and CVD in patients with LN. With growing use of biologics and new calcineurin inhibitors, future studies are worthwhile to evaluate how these novel therapeutics will attenuate the CV risk factors and CVD in patients with LN.
Lastly, study of hard CVD events and mortality is prone to survivorship bias, as only survivors could be studied, while data of non-survivors are overlooked. Results are also potentially confounded by age—an important risk factor for CVD and mortality, as patients in the LN group were generally younger than the non-LN group (online supplemental material 4).