Gustafsson Johanna T, Herlitz Lindberg Marie, Gunnarsson Iva, Pettersson Susanne, Elvin Kerstin, Öhrvik John, Larsson Anders, Jensen-Urstad Kerstin, Svenungsson Elisabet
Unit of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Department of Clinical Physiology, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2017 Apr 17;12(4):e0174572. doi: 10.1371/journal.pone.0174572. eCollection 2017.
Systemic lupus erythematosus (SLE), is a heterogeneous disease which predominantly affects young females (90%). SLE is associated with a shorter life expectancy than in the general population. Standardized mortality ratios (SMR) of 2.4 have been reported, which is comparable to diabetes. In modern societies cardiovascular disease (CVD) is the major cause of premature mortality. Accelerated atherosclerosis is generally assumed to be the underlying cause for SLE related CVD. However, previous studies diverge regarding whether atherosclerosis is more common in SLE than in controls. With this in mind and based on own clinical experience we hypothesized that accelerated atherosclerosis is not a general feature of SLE, but prevails in SLE subgroups.
281 SLE patients and 281 individually age and sex matched population controls, were investigated clinically. Fasting blood samples and risk factor data were collected. All participants were subject to B-mode ultrasonography of the carotid arteries. Carotid plaque occurrence and mean intima media thickness (mIMT) were recorded. Two SLE subgroups previously described to be at high CVD risk; 1) patients with nephritis and 2) patients with anti-phospholipid antibodies (aPL), and one subgroup reported to be at comparatively lower CVD risk; patients positive for Sjögren´s syndrome antigens A/B (SSA/SSB) antibodies were analyzed separately in comparison with their respective matched controls.
Median age was 49 (IQR 36-59) years, 93% were females. Manifest CVD; ischemic heart, cerebro- and peripheral vascular disease, prevailed in patients (12% vs. 1%, p<0.0001). Overall plaque prevalence did not differ (20% vs. 16%), but patients had slightly higher mIMT than controls (0.56 vs. 0.53 mm, p<0.0033). After age adjustment plaques, but not mIMT, remained associated with previous CVD events. Therefore we focused further analyses on plaques, a more robust measure of atherosclerosis. Patients with nephritis (40%), but neither aPL (25%) nor SSA/SSB (40%) positive patients, had more plaques than their respective controls (23% vs. 11%, p = 0.008). Notably, patients with nephritis were younger than other SLE patients (45 vs.49 years, p = 0.02). To overcome the confounding effect of age we performed an age-matched nested case-control analysis, which demonstrated that patients with nephritis had twice as often plaques (23%) as both non-nephritis patients (11%, p = 0.038) and controls (12%, p = 0.035).
In SLE excess carotid plaques are essentially confined to the SLE subgroup with nephritis. This subgroup had plaques twice as often as age-matched non-nephritis SLE patients and population controls. Non-nephritis SLE patients, including the aPL positive subgroup, which has a high CVD risk, had similar prevalence of plaques as controls. To prevent later CVD events, this novel observation calls for risk factor screening and initiation of anti-atherosclerotic treatment selectively in SLE nephritis patients. Preferably at nephritis onset, which is often at a young age. In a general perspective this study demonstrates the importance to perform careful clinical subgroup analyses when investigating heterogeneous, hitherto not clearly defined, conditions like SLE.
系统性红斑狼疮（SLE）是一种异质性疾病，主要影响年轻女性（90%）。与普通人群相比，SLE患者的预期寿命较短。据报道，其标准化死亡率（SMR）为2.4，与糖尿病相当。在现代社会，心血管疾病（CVD）是过早死亡的主要原因。一般认为，加速动脉粥样硬化是SLE相关CVD的潜在原因。然而，先前的研究在动脉粥样硬化在SLE患者中是否比对照组更常见这一问题上存在分歧。考虑到这一点并基于自身临床经验，我们推测加速动脉粥样硬化并非SLE的普遍特征，而是在SLE亚组中更为常见。
对281例SLE患者和281例年龄及性别匹配的人群对照进行临床研究。采集空腹血样和危险因素数据。所有参与者均接受颈动脉B型超声检查。记录颈动脉斑块的发生情况和平均内膜中层厚度（mIMT）。对先前描述的两个CVD高风险SLE亚组；1）肾炎患者和2）抗磷脂抗体（aPL）阳性患者，以及一个据报道CVD风险相对较低的亚组；干燥综合征抗原A/B（SSA/SSB）抗体阳性患者，分别与各自匹配的对照组进行分析。
中位年龄为49岁（四分位间距36 - 59岁），93%为女性。明显的CVD；缺血性心脏病、脑血管和外周血管疾病，在患者中更为常见（12%对1%，p<0.0001）。总体斑块患病率无差异（20%对16%），但患者的mIMT略高于对照组（0.56对0.53mm，p<0.0033）。年龄调整后，斑块而非mIMT，仍与既往CVD事件相关。因此，我们进一步将分析重点放在斑块上，这是动脉粥样硬化更可靠的指标。肾炎患者（40%），但aPL阳性患者（25%）和SSA/SSB阳性患者（40%）均未比各自的对照组有更多斑块（23%对11%，p = 0.008）。值得注意的是，肾炎患者比其他SLE患者年轻（45对49岁，p = 0.02）。为克服年龄的混杂效应，我们进行了年龄匹配的巢式病例对照分析，结果显示肾炎患者有斑块的几率是非肾炎患者（11%，p = 0.038）和对照组（12%，p = 0.035）的两倍（23%）。
在SLE患者中，颈动脉斑块过多主要局限于患有肾炎的SLE亚组。该亚组有斑块的几率是年龄匹配的非肾炎SLE患者和人群对照的两倍。非肾炎SLE患者，包括具有高CVD风险的aPL阳性亚组，其斑块患病率与对照组相似。为预防后期CVD事件，这一新发现要求对SLE肾炎患者进行危险因素筛查并选择性地启动抗动脉粥样硬化治疗。最好在肾炎发病时进行，此时患者通常较为年轻。从总体角度来看，本研究表明在研究像SLE这样异质性、迄今尚未明确界定的疾病时，进行仔细的临床亚组分析非常重要。
