Editorial article
Systemic lupus erythematosus today
Lupus eritematoso sistémico a día de hoy
José Mario Sabio
Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Virgen de las Nieves, Granada, Spain
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Its pathogenesis is complex and not well known. In general terms it is due to a primary abnormality of the innate and adaptive immune response leading to the appearance of autoreactive T and B cells and circulating autoantibodies, which results in the total loss of self-tolerance. This abnormal immune response starts in genetically predisposed individuals (to date more than 30 susceptibility genes have been identified, such as <span class="elsevierStyleItalic">STAT4, IRF5</span> and <span class="elsevierStyleItalic">ITGAM</span>) after exposure to certain environmental, hormonal and emotional factors.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Compared to other chronic diseases, SLE is a rare disorder. A prevalence of 30 cases/10<span class="elsevierStyleSup">5</span> inhabitants and an incidence rate of 2.3 cases/10<span class="elsevierStyleSup">5</span> inhabitants per year has been estimated in Spain,<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">3,4</span></a> rates that are similar to those found in neighbouring countries.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">5</span></a> Despite this low prevalence, its relative strain on health care activity and the economic costs it generates are not negligible. While treatment of lupus is primarily outpatient, during the 2005–2008 period SLE represented 0.3% of all inpatients for Internal Medicine services in Spain.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> In addition, the average stay and the economic cost per admission were higher than the average of those admitted for other processes.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> A retrospective Spanish study estimated that during the 2008–2010 period the average annual health costs associated with the control of SLE was €4833, of which 47% corresponded to hospitalisations, 30% to treatment with medications, 12% to consultations with other specialists and 11% to complementary tests.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">8</span></a> However, the real cost is much higher, since indirect costs of lost productivity or disability benefits are not included, which could be up to two-thirds of total spending.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The prognosis of SLE has improved considerably in recent decades. In a Canadian cohort study, the standardised mortality rate decreased from 12.6 during the 1970–1978 period to 3.5 during 1997–2005.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> Various factors have contributed to this decrease, although quantifying the importance of each of them separately is difficult. Early diagnosis, through the development and widespread use of autoimmunity tests, has allowed the disease to be treated in its early stages, preventing the onset of chronic damage, which is closely associated with a worse prognosis. Another important milestone was the introduction of protocols for the treatment of lupus nephritis based on the use of glucocorticoids and cyclophosphamide, although recently shorter and safer, but equally effective, guidelines have been developed.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">11</span></a> The rational use of corticosteroids at doses much lower than historically recommended<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> has reduced the toxicity and chronic damage caused by this drug. Recently, the use of antimalarials in all SLE patients has been recommended regardless of the severity and affected organs. Since this has been associated with lower mortality,<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> the impact this measure will have on survival should be evaluated at a later date. Although the therapeutic arsenal for SLE is limited, during the last decade 2 medications that have contributed to better control of lupus activity, even in refractory cases, have been released. Belimumab – the only medication that has been approved specifically for the treatment of SLE – is indicated for now as adjunctive therapy in patients with clinical and serologically active lupus and who are resistant to conventional treatment, although new indications are expected soon.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> Despite the less than satisfactory results obtained in some clinical trials, rituximab is often used off-label in refractory cases; it has also proven to be at least as effective as mycophenolate and cyclophosphamide in inducing remission of lupus nephritis.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a> As a result of these and other advances, the mortality pattern of SLE has changed in recent years.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> While during the 70s the main cause of death was renal involvement, mortality attributed to SLE activity has currently decreased, while infections and cardiovascular disease (CVD) have become more relevant. The main risk factor for developing an infection continues to be immunosuppressive therapy, even with moderate doses of glucocorticoids.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> However, despite being a major problem, the incidence of serious infections has declined when compared with historical cases. Prevention through the use of vaccines in risk patients, screening for infections and use of chemoprophylaxis in very immunosuppressed patients or those who will be subjected to a potent immunosuppressive therapy<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> has also contributed to this decline. Another major cause of death in SLE are thrombotic events, which in the Euro-Lupus cohort accounted for 26% of all deaths.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> Improved standardisations of laboratory methods for the detection and quantification of antiphospholipid antibodies (aPL), the identification of new prothrombotic autoantibodies, a better indication of antiplatelet and anticoagulation, and the incorporation of new oral anticoagulants will very probably contribute to the decline in mortality because of this cause. In this sense, the RAPS study is underway, a randomised controlled, Phase II/III clinical trial which aims to determine the efficacy and safety of rivaroxaban compared to warfarin in patients with antiphospholipid syndrome associated or not to SLE.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a> Haemodialysis and access to kidney transplant programmes have also been crucial for the survival of patients who have developed chronic renal failure. Finally, there is no doubt that an improved overall health care encouraged by health systems has also contributed decisively to improve the prognosis of SLE.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Patients suffering from lupus are more likely to have certain comorbidities associated with the disease itself or its treatment, although it is not always possible to separate the two components. These conditions have become important in recent years as a result of increased life expectancy. Thus, the comprehensive treatment of the lupus patient should not only include the control of lupus activity, but also ways of identifying, preventing and/or treating each of these comorbidities, as they constitute an important source of chronic damage and mortality. Lupus patients have between 2 and 10 times more risk of acute myocardial infarction and 2 times more risk of suffering a stroke as a result of an early and accelerated atherosclerosis process whose mechanism is not entirely known.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a> In this complex process, traditional cardiovascular risk factors, inflammatory mediators, autoimmune mechanisms, some medications and alterations of the endothelium repair mechanisms all participate.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a> Contrary to the trend observed in the general population, mortality due to CVD in SLE has experienced a slight increase in recent decades. This could be partially due to the fact that CVD is now easier to identify because better diagnostic techniques are available; whereas in previous decades some cardiovascular deaths could have been wrongly attributed to SLE or some other disease. 6–12% of lupus women have osteoporotic fractures, representing a 5-fold higher risk. The aetiology is multifactorial: in addition to the classic risk factors, other factors related to SLE could be involved, such as inflammation (TNF, oxidised LDL), serologic factors (presence of anti-Sm and absence of anti-Ro), medications and metabolic factors (hyperhomocysteinaemia and vitamin D deficiency).<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> Vitamin D deficiency is very common in SLE due to low exposure to sunlight, the use of photoprotection, a higher prevalence of kidney failure and some medications that can interfere with the patient's metabolism. Recent studies have correlated low levels of vitamin D with increased activity, fatigue and arteriosclerosis.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a> However, it has not been possible to unequivocally establish whether the use of vitamin D supplements can reverse these disorders, as results from several clinical trials have been contradictory. SLE patients may be at increased risk of malignancies, especially lymphomas and non-Hodgkin's cervical cancer. It could be due to the reactivation of latent virus as a result of the maintained immunosuppression, hyperstimulation of lymphocytes and long-term exposure to certain medications such as cyclophosphamide.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">23</span></a> There are no guidelines for the screening of neoplasia in SLE, so the recommendations given for the general population should be followed. Fertility in lupus women is not affected, but they are more likely to have early menopause and ovarian failure. Pregnancy can worsen the disease, so it should be discouraged in women whose activity is not well controlled. Pregnant women who suffer from lupus are more at risk of having obstetric complications such as abortions, foetal death, preeclampsia and preterm delivery, and their foetuses may have intrauterine growth retardation and congenital heart block. The risk depends on several factors at the time of conception, such as the presence of lupus nephritis, high activity, hypertension and aPL. Although not formally contraindicated, hormonal contraception should be used with caution in lupus women with risk factors for thrombosis and avoided when they have aPL.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">24</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Despite the good life expectations, SLE is a chronic, debilitating and disabling disease that can have a negative impact on physical and mental health, as well as social, psychological, economic, emotional and labour impacts. Most studies point to fatigue, pain and depression as the main determinants of quality of life, not lupus activity and chronic damage, which would contribute only marginally.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a> Improving patients’ quality of life has become a priority objective in the treatment of SLE, so it should be investigated with validated instruments. After all, patients not only aspire to live longer, but to live better.</p><p id="par0030" class="elsevierStylePara elsevierViewall">SLE is a complex, multifaceted and chameleonic disease; clinical experience is a determining factor in its treatment. Thus, the creation of specific units for this and other autoimmune diseases is fully justified, and not only from a health care perspective, but also for research and teaching. But at the same time, given its enormous heterogeneity and the numerous overlaps with other areas of medicine, treatment of lupus patients must be multidisciplinary.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The interest SLE is currently stirring among the scientific community is indisputable, as evidenced by the significant research into it taking place. The search for new, more sensitive and specific biomarkers for early diagnosis and to monitor activity and tissue damage, and the effectiveness of treatments is of special interest. In addition, a better understanding of the pathophysiology, genetics and epigenetics of SLE is facilitating the identification of new therapeutic targets, and the design of new highly specific biological treatments, including epratuzumab and sifalimumab, with ongoing Phase III clinical trials should be mentioned.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">26,27</span></a> Finally mesenchymal cells, whose immunomodulatory effect has been demonstrated in other autoimmune diseases, offers a promising therapeutic alternative.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Since the thirteenth century, when Rogerius first used the term “lupus” to describe the skin manifestations of this disease until today, the history of SLE has travelled an arduous but exciting journey marked by decisive progress and not a few failures. Even with problems and limitations, there is no doubt that the imminent future we can offer our lupus patients is more than encouraging.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Sabio JM. Lupus eritematoso sistémico a día de hoy. Med Clin (Barc). 2016;146:160–162.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:28 [ 0 => array:3 [ "identificador" => "bib0145" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Advances in lupus genetics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T.B. 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