Definitions of and contributions to cardiovascular disease in systemic lupus erythematosus

Abstract

Patients with systemic lupus erythematosus (SLE) have a significantly increased risk of cardiovascular disease (CVD). Increased prevalence of atherosclerosis may explain part of this enhanced risk, but SLE related CVD can also result from other mechanisms. Vascular events may be the result of several pathophysiologic mechanisms; some can be caused by atherosclerosis, others may be primarily thrombotic, and some may be due to ongoing inflammation. The traditional risk factors are of importance for the development of CVD in lupus. However, lupus-related factors, such as endothelial dysfunction and inflammation, renal impairment and disease activity, lupus phenotype, autoantibodies and genetic predisposition are equally or even more important. Risk factors may also contribute separately or in combination to increase the risk of atherosclerosis and clinical CVD in SLE. Studies investigating risk factors for CVD in SLE vary with respect to definition of outcome, it is, e.g. common that the terms atherosclerosis and clinical CVD are used interchangeably. Varying definitions and outcomes may thus explain divergent results of different studies and make comparisons difficult. This review summarizes some of the current knowledge regarding risk factors and mechanisms for atherosclerosis and clinical CVD in SLE. Aspects on the importance of CVD definitions and outcomes are briefly discussed.     

B-Cell-Targeted Therapy for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by a myriad of immune system aberrations, most likely resulting from pathogenic autoantibody production, immune complex deposition, and subsequent end-organ damage. B cells play a key role in the pathogenesis; therefore, B-cell-targeted therapies, including B-cell depletion and blockage of B-cell survival factors such as B-lymphocyte stimulator (BLyS), are potential therapeutic targets for SLE. In uncontrolled clinical trials from approximately 20 studies, rituximab--a mouse-human chimeric anti-CD20 monoclonal antibody that effectively depletes B cells--has been demonstrated to reduce disease activity and decrease serum autoantibodies, with a clinical response of 86% in a case series of approximately 400 SLE patients with refractory disease, with or without concomitant use of cyclophosphamide. Epratuzumab, a humanized anti-CD22 monoclonal antibody that partially depletes B cells, has also been shown to reduce disease activity but not to decrease autoantibody levels in patients with moderately active SLE. Randomized controlled phase I/II trials in patients with active SLE have documented that belimumab, a humanized anti-BLyS monoclonal antibody, reduces B-cell numbers, inhibits disease activity and decreases anti-double-stranded DNA autoantibody in SLE patients. All these therapies are well tolerated, but accompanying infectious complications have been observed. Other B-cell-targeted therapies such as 'humanized' monoclonal antibodies to CD20 (e.g. ocrelizumab) and agents that interrupt B-cell/T-cell interactions also have potential, and the efficacy of these, along with rituximab, belimumab and epratuzumab, needs to be determined by randomized controlled trials.     

Belimumab for the treatment of systemic lupus erythematosus

Given their pivotal role in autoantibody production, B-cells have become an attractive therapeutic target in systemic lupus erythematosus (SLE). Belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (BLyS), a B-cell survival factor, was licensed in 2011 for the treatment of autoantibody-positive SLE. The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients compared to placebo with standard therapy. Overall, belimumab has been found to be safe and well tolerated. While the BLISS-52 and BLISS-76 studies are the largest clinical trials in SLE to date, they mainly focused on musculoskeletal, mucocutaneous, hematologic and general constitutional features of the disease. Patients with severe lupus nephritis and severe central nervous system disease were excluded from these trials. Studies of belimumab in lupus nephritis are ongoing that may clarify the role of this agent in the clinical management of SLE.     

Belimumab: A Guide to Its Use in Systemic Lupus Erythematosus

Belimumab (Benlysta?), a fully human recombinant IgG1λ monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells, is indicated for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity despite receiving standard therapy. In multinational trials, significantly more belimumab recipients than placebo recipients achieved an SLE Responder Index response at 52 weeks.     

Autoimmunity,oxidized LDL and cardiovascular disease

Atherosclerosis is the major cause of cardiovascular disease (CVD) and in addition to established risk factors as smoking, hypertension, diabetes and dyslipidemia, inflammation and autoimmune reactions have been much discussed recently. Several lines of evidence indicate that also inflammation and autoimmune reactions are highly relevant in atherosclerosis and CVD. Inflammatory cells and cytokines are present in lesions, already at an early stage; animal experiments suggest that immune reactions, though not necessary for development of atherosclerosis, can modulate disease development and systemic inflammation is associated with an enhanced risk of CVD. The enhanced risk of CVD in a major autoimmune disease, systemic lupus erythematosus (SLE), is therefore highly relevant, and in addition to being an important clinical problem, SLE-related CVD could give insights into the nature of autoimmunity in atherosclerosis and CVD in general. We recently defined traditional and non-traditional risk factors for CVD in SLE. These include increased atherosclerosis (as determined by intima-media thickness of carotid artery); raised oxidized low density lipoprotein (OxLDL) and autoantibodies to OxLDL; dyslipidemia with raised triglycerides and Lp(a) and decreased HDL-cholesterol concentrations; raised systemic inflammation; presence of anti-phospholipid antibodies including lupus anticoagulant, homocysteine-levels and more frequent osteoporosis. Disease duration, smoking, blood pressure or diabetes mellitus did not differ significantly between the groups. Taken together, immune reactions are highly relevant in atherosclerosis, and patients with autoimmune disease like SLE are at high-risk of CVD. If confirmed prospectively, non-traditional risk factors like OxLDL in the circulation, autoantibodies against OxLDL and phospholipids and inflammation could lead to new therapeutic strategies and insight into disease mechanisms.     

Do biological agents improve health-related quality of life in patients with systemic lupus erythematosus? Results from a systematic search of the literature

Despite an unprecedented rise in the number of biological therapies developed for systemic lupus erythematosus (SLE) during the last decades, most randomised clinical trials (RCTs) have failed to reach their primary efficacy endpoint. These endpoints mainly constitute composite outcomes that encompass disease activity indices derived from clinician-reported and laboratory data and do not necessarily reflect the patient perspective, as symptoms that represent major concerns to patients, such as fatigue, are seldom part of the evaluation. To overcome this limitation, patient-reported outcomes (PROs) constitute useful tools for evaluating the effect of an intervention on facets that are particularly relevant for the patients. In the present review, we performed a systematic literature search aiming to examine the effect of biological therapies on SLE patients' health-related quality of life (HRQoL) and fatigue in RCT and real-life settings. We summarised results concerning 14 different biological agents, the majority of which targeting B cells or type I interferons, and discuss strategies that have been used to analyse HRQoL data, putting emphasis on minimal clinically important differences and the potential use of PROs as distinct targets in treat-to-target approaches. Lastly, we discuss differences between generic and disease-specific PRO measures and highlight the need of using a combination thereof aiming to capture the patient perspective in a comprehensive manner.     

造血干细胞移植治疗系统性红斑狼疮的进展

系统性红斑狼疮是一种病因未明的自身免疫性疾病,基本上由自身抗体和免疫复合物介导致病.随着医学在基因水平上不断发展,对于重症SLE不能耐受传统疗法,HSCT目前已是公认的潜在治疗手段之一.从报道HSCT治疗严重AID至今,大约有20个国家的700个患者接受了临床Ⅰ/Ⅱ试验.研究认为,大剂量免疫抑制和移植后免疫重建可能是使SLE缓解的机制.经过10年的临床试验,国内对HSCT治疗手段不断成熟,以北京协和医院为首.虽有明显改善SLE病情,但随诊时期不长,仍存在着许多需要进一步解决的问题,HSCT给予那些难治的其他疗法无效的患者提供了"补救疗法",是否更有效,仍需要进一步进行随机化控制实验.     

Physical activity and autoimmune diseases: Get moving and manage the disease

Physical activity, by definition, is any skeletal muscle body movement that results in energy expenditure. In the last few decades, a plethora of scientific evidences have accumulated and confirmed the beneficial role of physical activity as a modifiable risk factor for a wide variety of chronic diseases including cardiovascular diseases (CVDs), diabetes mellitus and cancer, among others. Autoimmune diseases are a heterogeneous group of chronic diseases, which occur secondary to loss of self-antigen tolerance. With the advent of biological therapies, better outcomes have recently been noted in the management of autoimmune diseases. Nonetheless, recent research highlights the salient role of modifiable behaviors such as physical inactivity on various aspects of the immune system and autoimmune diseases. Physical activity leads to a significant elevation in T-regulatory cells, decreased immunoglobulin secretion and produces a shift in the Th1/Th2 balance to a decreased Th1 cell production. Moreover, physical activity has been proven to promote the release of IL-6 from muscles. IL-6 released from muscles functions as a myokine and has been shown to induce an anti-inflammatory response through IL-10 secretion and IL-1β inhibition. Physical activity has been shown to be safe in most of autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel diseases (IBD), as well as others. Additionally, the incidence of RA, MS, IBD and psoriasis has been found to be higher in patients less engaged in physical activity. As a general trend, patients with autoimmune diseases tend to be less physically active as compared to the general population. Physically active RA patients were found to have a milder disease course, better cardiovascular disease (CVD) profile, and improved joint mobility. Physical activity decreases fatigue, enhances mood, cognitive abilities and mobility in patients with MS. In SLE patients, enhanced quality of life and better CVD profile were documented in more physically active patients. Physically active patients with type 1 diabetes mellitus have a decreased risk of autonomic neuropathy and CVD. Both fibromyalgia and systemic sclerosis patients report decreased disease severity, pain, as well as better quality of life with more physical activity. Further, SSc patients improve their grip strength, finger stretching and mouth opening with increased level of exercise. The purpose of this paper is to review the clinical evidence regarding the safety, barriers to engagement, and impact of physical activity on autoimmune diseases.     

B-Cell Targeted Therapies in Systemic Lupus Erythematosus

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the formation of autoantibodies that target a variety of self antigens. B cells are fundamental to the development of these antibodies and are a target for intervention in the disease. This review discusses four therapies that target B cells by inducing B-cell depletion, reduction in B-cell proliferation and differentiation, or modulation of B-cell function. Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes B cells but not plasma cells. Systematic reviews of open label studies, particularly in lupus patients refractory to conventional therapy, have suggested that rituximab can be an effective treatment for non-renal lupus and lupus nephritis. However, randomized, double-blind, controlled trials comparing rituximab with placebo in addition to standard of care therapy for non-renal lupus and lupus nephritis over 12 months failed to demonstrate efficacy using the planned primary endpoints, although there were some post-hoc analyses suggesting that rituximab may have beneficial effects that would be worthy of further study as no significant toxicity has been demonstrated. Treatment with belimumab, a humanized monoclonal antibody targeted against B lymphocyte stimulator (BLys), was more efficacious than placebo and had no significant increase in adverse events in two non-renal, phase III lupus trials when given in addition to standard of care therapy for 52 weeks. Belimumab is licensed for the management of lupus in the US and in Europe. Atacicept is a humanized fusion protein that binds BLys and APRIL (a proliferation-inducing ligand) that might be more effective than belimumab in the management of lupus. Unfortunately a phase II/III trial of atacicept in lupus nephritis had to be stopped due to the development of low immunoglobulin levels and pneumonias in some patients. However, in retrospect these complications may have been due to concomitant treatment with mycophenolate mofetil and results of a 52-week, non-renal, phase III trial with atacicept are awaited. Epratuzumab is a humanized monoclonal antibody that targets CD22 on B cells and results in modulation of B-cell function and migration, as CD22 regulates adhesion and inhibits B-cell receptor (BCR) signalling. Epratuzumab at a cumulative dose of 2,400 mg over 4 weeks has been shown to improve lupus disease activity compared with placebo 12 weeks after initiation of therapy in a phase II study, and a 12-month phase III study is on-going. B-cell targeted therapies are an attractive prospect for treating lupus disease and the results of current phase III trials are eagerly awaited. Finding the most appropriate trial design to demonstrate efficacy in lupus trials has been a challenge. The SRI (SLE response index) used in the belimumab studies and the BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) used in the epratuzumab studies are currently the promising trial designs for non-renal studies. For lupus nephritis it is important that trials are of adequate duration to be able to demonstrate benefit of new therapies over conventional therapy.     

Refractory disease in systemic lupus erythematosus

There is no definition or guidelines for refractory disease (RD) in Systemic Lupus Erythematosus (SLE). However, new therapies have been tested mainly in refractory patients. The concept, like the disease, is complex and implies deeper knowledge on the disease pathogenesis and patients' subsets. RD is not included in current activity indices of the disease, what raises the question of how are we monitoring its response to new drugs. In this paper, we analyse some concepts considered important for the global definition of RD in SLE and in some specific organ involvements, excluding lupus nephritis. Management issues will be addressed also. Finally, we review therapeutic options in particular subsets of the disease, namely, cutaneous, articular, haematological and neuropsychiatric lupus. Crucial to the management of a patient suspected to be refractory is an accurate diagnosis, assuring that the persistent clinical manifestations are derived primarily from SLE and not from a concomitant or alternative process. Likewise, certainty about the patient compliance with the therapy prescribed is a frequent unrecognized problem that erroneously might lead to a classification of RD. Therapy of RD for SLE, in general and in most particular involvements, is currently based mainly on the clinician's own experience and judgement, with few randomized trials effectively addressing the issue. In such a heterogeneous disease, consideration of approval of drugs for single-organ indications may pave the way for new therapies. Better biomarkers are needed to add accuracy to the currently used activity indices in order to monitor RD and consolidate its definition. Prospective studies directed to RD in the main SLE involvements are needed to improve our understanding on the management of the disease and foster the development of targeted new drugs.     

Annexin A5 in cardiovascular disease and systemic lupus erythematosus

Atherosclerosis, a major cause of disease and death from cardiovascular disease (CVD), is an inflammatory disease characterized by T cell and monocyte/macrophage infiltration in the intima of large arteries. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in systemic lupus erythematosus (SLE), often considered a prototypic autoimmune disease. A combination of traditional and non-traditional risk factors, including dyslipidemia, inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. aPL are highly thrombogenic, and possible mechanisms include direct effects of aPL on endothelial and other cells, and interference with coagulation reactions.

More than a thousand proteins of the annexin-superfamily are expressed in eukaryotes. Annexins are ubiquitous, highly conserved, predominantly intracellular proteins, widely distributed in tissues. Annexin A5 (ANXA5) is an important member of the annexin family due to its antithrombotic properties. These are believed to be caused by it forming a two-dimensional protective shield, covering exposed potentially thrombogenic cell surfaces. Recently, ANXA5 has been implicated in SLE since aPL interfere with ANXA5 binding to placental trophoblasts, causing microthrombosis and miscarriage, a rather common complication in SLE. We recently demonstrated that ANXA5 may play a role in CVD and is abundant in late-stage atherosclerotic lesions. Sera from SLE-patients with a history of CVD inhibited ANXA5 binding to endothelium, caused by IgG antibodies, to a significant degree aPL. This review will focus on potential involvement of ANXA5 in pathogenesis of CVD, particularly caused by underlying atherosclerosis and atherothrombosis.     

Cyclosporin

Systemic lupus erythematosus (SLE) is a complex multisystem disease which is characterised by formation of antibodies to ;self' antigens. It often presents as a mild, controllable disorder but may become severe and is potentially life threatening, particularly when major organs/systems are involved. Although treatments for severe SLE are available (e.g. corticosteroids +/- cytotoxic/immunosuppressive agents), high dose or long term therapy with these agents is associated with serious and potentially life-threatening adverse effects and is not effective in all patients. Several noncomparative trials in patients with severe SLE refractory to conventional treatment have demonstrated that low dose cyclosporin in combination with steroids (and occasionally with additional cytotoxic/immunosuppressive agents) can provide long term disease improvement or remission and, importantly, a reduction in steroid use. Clinical benefits have also been observed with the cyclosporin-steroid combination in patients with lupus nephritis, most of whom had failed to respond to conventional treatment. Nephrotoxicity has been documented in some patients receiving cyclosporin for SLE, but initial biopsy data suggest that this complication is not a treatment-limiting factor for most patients. Nevertheless, the risk of cyclosporin-induced nephrotoxicity and the clinical implications of this effect have yet to be accurately assessed in large numbers of patients with SLE and definitive data may be difficult to obtain. Although initial efficacy and tolerability data from patients with lupus nephritis are favourable, the drug is more likely to be used in patients whose kidney function remains relatively unimpaired. Thus, available noncomparative data suggest that cyclosporin is useful in the treatment of patients with severe refractory SLE or those who cannot tolerate conventional therapy, but definitive comparative data are lacking. Any decision to prescribe cyclosporin for such patients will need to take into account the potential benefits of the drug, the clinical implications of uncontrolled disease and the risk of nephrotoxicity in individual patients.     

Dyslipidemia in systemic lupus erythematosus

Cardiovascular disease is one of the major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Accelerated atherosclerosis is related to traditional (age, hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, and positive family history) and non-traditional, disease-related factors. Traditional risk factors are still more prominent in patients with lupus, as both hypertension and hypercholesterinemia were independently associated with premature atherosclerosis in several SLE cohorts. In this work, the authors summarize the epidemiology of dyslipidemia in lupus patients and review the latest results in the pathogenesis of lipid abnormalities. The prevalence of dyslipidemia, with elevations in total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), and apolipoprotein B (ApoB), and a reduction in low-density lipoprotein (LDL) levels are about 30% at the diagnosis of SLE rising to 60% after 3 years. Multiple pathogenetic mechanism is included, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can suppress HDL and increase TG, auto-antibodies can cause the injury of the endothelium, lipoprotein lipase (LPL) activity can be reduced by circulating inflammatory mediators and antibodies, and increased oxidative stress may trigger a wide range of pro-atherogenic lipid modifications. As a major risk factor, dyslipidemia should be treated aggressively to minimize the risk of atherosclerosis and cardiovascular events. Randomized controlled trials with statins are controversial in the detention of atherosclerosis progression, but can be favorable by inhibiting immune activation that is the arterial wall and by decreasing lupus activity.     

Periodontal disease as a risk factor for cardiovascular disease: suggestion of a further link in systemic lupus erythematosus

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Due to either infection or disease activity, elevated levels of inflammatory markers and up-regulation of the autoimmune process can contribute to the development of atherosclerosis in SLE patients. Periodontal diseases are among the most prevalent chronic infections in humans and are characterized by pathogen-induced oral inflammatory disease affecting the supporting tissues of teeth. Several cytokines capable of inducing systemic effects are produced during the course of this infection. The presence of these cytokines can be verified by changes in the levels of C-reactive protein (CRP). Periodontal disease is a well-known risk factor for atherosclerosis. The potential for beneficial prevention of CVD events through the use of periodontal treatment has been previously recommended. This review reinforces the hypothesis that periodontal infection could be a risk factor for CVD in patients diagnosed with SLE, and suggests that by reducing the progression of this oral infection, levels of inflammatory markers common to both diseases (SLE and periodontal disease) would likely decrease.     

Decreased levels of autoantibodies against apolipoprotein B‐100 antigens are associated with cardiovascular disease in systemic lupus erythematosus

Increased production of autoantibodies is a characteristic feature of systemic lupus erythematosus (SLE) and there is evidence that several of these autoantibodies may contribute to increased cardiovascular disease (CVD) in SLE. Autoantibodies against the apolipoprotein (apo) B‐100 peptides p45 and p210 have been associated with a lower CVD risk in non‐SLE cohorts. The aim of the present study was to investigate how SLE affects the occurrence of these potentially protective autoantibodies. The study cohort consisted of 434 SLE patients and 322 age‐ and sex‐matched population controls. Antibodies against native and malondialdehyde (MDA)‐modified p45 and p210 were measured by enzyme‐linked immunosorbent assay (ELISA). SLE patients had significantly lower levels of p210 immunoglobulin (Ig)G and p45 IgM (both the native and malondialdehyde (MDA)‐modified forms). SLE patients with manifest CVD (myocardial infarction, ischaemic cerebrovascular disease or peripheral vascular disease) had lower levels p210 IgG and p45 IgM than SLE patients without CVD. Decreased levels of these autoantibodies were also observed in SLE patients with permanent organ damage, as assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SDI). The present findings show that patients with SLE, a condition generally characterized by abundance of autoantibodies of multiple specificities, have reduced levels of antibodies against the apo B‐100 antigens p45 and p210 and that the levels of these antibodies are reduced further in SLE patients with CVD. These observations suggest the possibility that an impaired antibody‐mediated removal of damaged LDL particles may contribute to the development of vascular complications and organ damage in SLE.     

Systemic lupus erythematosus and hypertension

Systemic lupus erythematosus (SLE) is associated with a high burden of cardiovascular disease (CVD), which is in part imputed to classical vascular risk factors such as hypertension. Hypertension is frequent among patients with SLE and studies show it is more prevalent in SLE patients than in people without SLE. Despite the high frequency of hypertension in SLE patients, the pathophysiological mechanisms underlying the development of hypertension remain poorly understood. 24-h ambulatory blood pressure monitoring has emerged as a valuable tool in determining blood pressure (BP) in SLE patients in whom hypertension has been associated with damage accrual, stroke and cognitive dysfunction. Although prevalent, current guidelines neglect the specific management of hypertension in SLE patients in their recommendations. This review discusses the mechanisms that may lead to hypertension and the literature evaluating hypertension screening and management in SLE patients.     

Belimumab Therapy in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex heterogeneous disease, posing challenges to clinical trials. As in other autoimmune diseases, B-lymphocytes play a central role in lupus pathogenesis. The finding that selection and survival of B cells are controlled by a variety of signals, including those provided by the longevity factor BAFF (B-cell activating factor), also called BLyS (B-lymphocyte stimulator), led to preclinical trials that revealed that BAFF represents a promising therapeutic target for human lupus. Belimumab is a fully human monoclonal antibody directed against BAFF. Lessons learned from early clinical trials led to improved methods and success of phase III trials, with recruitment of patients with both clinically and serologically active disease, development and use of a novel SLE Responder Index, and progressive and special restrictions on immunosuppressive and corticosteroid use. These studies offer an attractive blueprint to conduct future clinical trials in SLE. The overall steroid-sparing ability and benefits of belimumab on musculoskeletal and mucocutaneous organ systems suggest that it has an impact on the clinical management of SLE patients. Future directions include studies to determine the role of belimumab in early SLE, as well as in renal or CNS involvement.     

The efficacy of novel B cell biologics as the future of SLE treatment: A review

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with wide ranging multi-systemic effects. Current understanding centralises B cells in SLE pathogenesis with clinical features resulting from autoantibody formation, immune complex deposition, antigen presentation and cytokine activation. Existing standard of care therapies generates adverse side effects; secondary to corticosteroid use and untargeted immunosuppression. The inability to uphold remission and abolish the disease process, in addition to the increasing numbers of patients seen with refractory disease with these therapies, has provoked the development of novel B cell biologics targeting specific pathogenic pathways fundamental to the SLE disease process.     

Vitamin D and systemic lupus erythematosus: an update

Vitamin D is a steroid hormone that, in addition to its actions on calcium and bone metabolism, exhibits a plethora of regulatory effects on growth, proliferation, apoptosis and function of the cells of the immune system that are relevant to the pathophysiology of systemic lupus erythematosus (SLE). Hypovitaminosis D is highly prevalent in SLE as a result of avoidance of sunshine, photoprotection, renal insufficiency and the use of medications such as glucocorticoids, anticonvulsants, antimalarials and the calcineurin inhibitors, which alter the metabolism of vitamin D or downregulate the functions of the vitamin D receptor. Low levels of vitamin D correlate with disease activity, and is associated with osteoporosis, fatigue and certain cardiovascular risk factors in SLE patients. This review updates the recent evidence on the relationship between vitamin D status and the onset, activity and complications of SLE, and summarizes the recommendations for vitamin D supplementation.