Childhood- and adult-onset lupus: an update of similarities and differences

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune rheumatic disease. Although its highest prevalence is among women of childbearing age, the disease is not confined within this population. A total of 15–20% of cases of SLE are diagnosed in children younger than 16 years (childhood-onset lupus). Although there have been few studies directly comparing childhood- to adult-onset lupus, there is substantial evidence to suggest that pediatric lupus patients display some differences in their disease profile compared with adult-onset populations. Overall, an increased male-to-female ratio, a higher prevalence of nephritis and CNS involvement necessitating a more sustained need for steroids and immnosuppressive drugs, and a higher prevalence of progression to end-stage renal disease are distinguishing features of childhood-onset lupus. In contrast, a higher prevalence of pulmonary involvement, arthritis and discoid lupus are reported in adult-onset SLE patients. Furthermore, childhood-onset lupus patients may experience a serious negative impact on their psychosocial and physical development, issues that pose extra challenges to healthcare providers. Growth delay, osteoporosis, the psychological effect of steroid-induced alterations of the physical image, and often poor treatment compliance are the issues that need to be addressed in pediatric lupus populations. In this review, we compare the epidemiological, clinical and laboratory features, and treatment options of childhood- and adult-onset lupus, and comment on the applicability of the instruments that measure activity, severity and cumulative disease damage in childhood-onset disease. In addition, we highlight special issues of concern for pediatric lupus patients, discussing the significance in the transition from pediatric to adult rheumatology care.     

Mechanisms of disease for the clinician: systemic lupus erythematosus

ObjectiveTo review the complex interactions and processes in systemic lupus erythematosus (SLE).Data SourcesBrief review of the important literature in peer-reviewed journals.Study SelectionStudies on the clinical and immunologic features, pathogenesis, epidemiology, laboratory evaluation, and treatment of SLE are included in this review.ResultsSLE may include a variety of disease entities, such as isolated cutaneous lupus, undifferentiated connective tissue disease, mixed connective tissue disease, and drug-induced lupus. There are many ongoing clinical trials in SLE patients of therapeutics with different mechanisms of cellular action, such as classic immunosuppression, cell depletion, antigen-specific immunomodulation, and targeting of antigen-nonspecific, immune-activating molecules. New immune cell–targeted therapies are now available that are specifically designed to block cellular pathways involved in disease pathogenesis.ConclusionThe practicing physician should understand the immunology, pathogenesis, laboratory evaluation, and updated treatment options when diagnosing SLE in their clinic or daily practice.     

The prevalence of antiphospholipid antibody syndrome among systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by excess autoantibody production. It typically affects women of childbearing age. Antiphospholipid antibody syndrome (APLAs) is associated with serious co-morbidity to mother and child characterized by recurrent vascular thrombosis and/or pregnancy associated morbidity. We reviewed SLE patients attending a specialist connective tissue disease clinic both to assess the occurrence of APLAs and its clinical presentations and to audit the effectiveness of screening for APL antibodies in a specialist clinic. 204 patients attended the newly established connective tissue disease outpatient clinic over a twenty-seven month period; 42 (34 female, 8 male) with a diagnosis of SLE. Ten patients (24%), eight female and 2 male with a median age of 38.5 years (range 20 to 64 years) fulfilled the ACR criteria for secondary APLAs (Table 2). The commonest clinical presentation was pulmonary embolus (five patients). Overall 37 patients (88%) with SLE were screened for APLAs during the study period: 94% of females and 62.5% of males were screened (for anticardiolipin antibodies, lupus anticoagulant or both), 27% had evidence of APLAs, 24% had positive antibodies but were asymptomatic. There is a significant occurrence of APLAs among SLE patients. Given the important clinical implications of this disorder including substantial risk of fetal loss and patient morbidity or mortality, routine screening of all SLE patients for APL antibodies is recommended.     

Fibromyalgia in systemic lupus erythematosus: prevalence and clinical implications

Fibromyalgia (FM) is common in SLE patients, and is the source of many of the symptoms and much of the disability in these patients. The association of FM and SLE may pose diagnostic dilemmas. Fibromyalgia does not correlate with SLE disease activity, but the clinical features of FM in these patients may contribute to a misinterpretation of lupus activity. The recognition of the association between SLE and FM is relevant to every physician who treats lupus patients.     

Rituximab: a promising therapy in systemic lupus erythematosus

Several trials of new immunologic agents in systemic lupus erythematosus (SLE) have recently been undertaken. Rituximab, a chimeric antibody directed against CD20 on B lymphocytes, has emerged as a promising therapy. Based upon preliminary data, clinical efficacy of rituximab has been documented in both pediatric and adult-onset SLE patients. The specific manifestations reported to be beneficially affected include lupus nephritis, arthralgia/arthritis, serositis, cutaneous vasculitis, mucositis, rashes, fatigue and neurologic symptoms. Although rituximab's mechanisms of action are incompletely understood, the effects of rituximab are likely mediated by antibody-dependent cell-mediated cytotoxicity and the induction of apoptosis. The resultant repopulation of B cells, alteration of abnormal B cell homeostasis and down-regulation of co-stimulatory molecules on both B and T cells all likely contribute to clinical efficacy. Good tolerability of rituximab is reported with rare serious side effects. The positive response to rituximab verifies a central role for B cells in SLE. This article highlights the clinical experience of rituximab therapy in both pediatric and adult-onset SLE. These data suggest a promising role for rituximab in the treatment of SLE. Further controlled trials and long-term outcome studies are imperative to further define its clinical application and to improve the care of patients.     

COVID-19 vaccine safety during pregnancy in women with systemic lupus erythematosus

COVID-19 vaccination has been shown to be safe in patients with systemic lupus erythematosus (SLE), but data on vaccine-associated adverse events (AEs) during the antenatal and lactation period are scarce or lacking. We investigated COVID-19 vaccination-related AEs in pregnant SLE patients from the COVAD study, a global esurvey involving 157 collaborators from 106 countries. A total of 9201 complete responses were extracted. Among 6787 (73.8%) women, we identified 70 (1.1%) who were exposed to at least one COVID-19 vaccine dose during pregnancy, 11 with SLE. Delayed onset (>7 days) vaccine-related AEs were triangulated with disease activity, treatment changes due to flare after vaccination, and COVID-19 infections in vaccinated pregnant women. Health-related quality of life and physical function was recorded using PROMIS. Age of patients ranged from 28 to 39 years; 5/11 women were of Asian origin. None of these patients reported major vaccine AEs or change in the status of their autoimmune disease. Although minor AEs were common, they did not impair daily functioning, and the symptoms resolved after a median of 3 (IQR: 2.5–5.0) days. All patients reported good to excellent health status. No adverse pregnancy outcomes were reported. Importantly, none of the patients reported thrombotic events post-vaccination, which provides reassurance in a patient population with a high risk for cardiovascular comorbidity and thrombosis, especially in the presence of antiphospholipid antibodies or the antiphospholipid syndrome, a considerable portion of SLE patients. Our findings provide reassurance and can contribute to informed decisions regarding vaccination in patients with SLE and high-risk pregnancies due to their background autoimmune disease. The risk/benefit ratio of COVID-19 vaccination appears favourable, with vaccines both providing passive immunisation to the fetus and active immunisation to the mother with no signals of exacerbation of the mother's autoimmune disease.     

Preventive strategies in systemic lupus erythematosus

Despite the improvement of systemic lupus erythematosus (SLE) survival observed in the last decades, the long-term prognosis of these patients remains poor mainly due to complications of the disease and/or of its treatment. Therefore, in order to improve SLE prognosis, we should try to avoid long-term complications by adopting, early in the disease course, some strategies directed to prevent infections, atherosclerosis and cancer. Moreover, since it has been shown that autoantibodies appear before clinical manifestations in SLE, the question of whether or not asymptomatic individuals with a reliable positive serology should be treated arises. Other than advising these individuals to avoid sun exposure, drugs implicated in drug-induced lupus and cigarette smoking, the use of vitamin D and hydroxychloroquine could be considered. Finally, early SLE diagnosis has led to a modification of disease clinical spectrum at disease onset with an increased frequency of mild disease manifestations over severe ones. Thus great effort should be made in order to identify early in the disease course risk factors for the development of severe SLE manifestations. Finally patients with mild disease carrying factors predictive of severe manifestations should be treated more aggressively than we have done up to now.     

The effect of systemic lupus erythematosus on pregnancy and pregnancy outcome.

This review provides an analysis of reports published since 1980 on the effect of systemic lupus erythematosus (SLE) on pregnancy and pregnancy outcome. The question whether pregnancy increases clinical flares and the severity of flares in patients with SLE during pregnancy has not been resolved because of difficulty in defining exacerbations of SLE and of preeclampsia. An analysis of major detailed reports indicates that maternal complications are reduced in patients who are in clinical remission prior to the onset of pregnancy compared with women with persistent disease activity. Complications are observed in 30%-50% of patients with inactive disease at onset of gestation. After exclusion of spontaneous abortions during the first trimester, fetal survival was 85%-90% in most reported case series. The best outcomes were reported in patients with inactive disease at onset of pregnancy. It seems likely that some maternal complications and fetal wastage in this population are related to anticardiolipin antibodies.     

Systemic lupus erythematosus in the elderly

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, characterized by multisystemic involvement. Late onset SLE represents a specific sub-group of the disorder, beginning above 50-65 years of age. The incidence of late onset SLE ranges in the interval of 12-18% and the course of the disease is considered to be more benign. According to several authors, skin manifestations, photosensitivity, arthritis and nephritis, occur rarely in the elderly patients with late SLE onset; prevalence of serositis, lung involvement and Sj?gren's syndrome were observed more often. Late onset SLE patients manifested higher rate of positive findings of rheumatoid factors, as well as of anti-Ro and anti-La antibodies; and the lower occurrence of anti-RNP antibodies and hypocomplementaemia. A slow onset of the disorder, non-specific manifestations at the beginning of the illness and less frequent prevalence of SLE in the elderly often result in late diagnosis. Treatment of the disease depends on its clinical manifestations. NSAID's, antimalarials or low doses of glucocorticoids are used for the less severe forms. Immunosuppressives and higher doses of glucocorticoids are the treatments of choice for more severe organ involvements and complications. A multidisciplinary approach is recommended for the treatment of late onset SLE patients.     

Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus.

Anti-double stranded (dsDNA) antibodies are of considerable diagnostic value and are thought to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Fluctuations in anti-dsDNA antibody levels are also used as markers for disease activity and exacerbations. In this study we sought to evaluate the anti-dsDNA antibody level in serum samples collected before the onset of SLE diagnosis. A total of 130 SLE patients were identified with stored serum samples available prior to diagnosis within the US Department of Defense serum repository. All 633 sera available from these patients were screened for anti-dsDNA antibodies using an enzyme linked immunosorbant assay (ELISA). Within this cohort 55% of cases had detectable anti-dsDNA antibodies prior to SLE diagnosis. The onset of anti-dsDNA antibodies ranged from 9.3 years before to within the same month as diagnosis (with a mean onset 2.7 years before diagnosis). In order to assess for fluctuations in anti-dsDNA levels relative to diagnosis, cases were selected with at least two positive samples, one within 6 months and a second greater than 6 months prior to diagnosis (n = 26). Seven of these cases also had samples available shortly after diagnosis (< or = 6 months) for comparison. Fifty-eight percent of the 26 cases developed a significant rise in anti-dsDNA antibody levels within 6 months of diagnosis. A significant decline in anti-dsDNA levels ensued after diagnosis (and following treatment with corticosteroids) in all seven cases with samples available. Patients with a significant rise in anti-dsDNA antibodies at diagnosis were more likely to have renal disease than those who did not (66.7% compared to 27.3%, chi2 =3.94, P<0.05). These data suggest that anti-dsDNA antibodies are present in SLE patient sera much earlier than previously suspected. In addition, the data are consistent with increases in anti-dsDNA levels contributing to the onset of clinical illness in some patients with SLE.     

A comprehensive review of the clinical approach to pregnancy and systemic lupus erythematosus

Nowadays, most of the young women affected by Systemic Lupus Erythematosus (SLE) can carry out one or more pregnancies thanks to the improvement in treatment and the consequent reduction in morbidity and mortality. Pregnancy outcome in these women has also greatly improved in the last decades. A correct timing for pregnancy (tailored on disease activity and established during a preconception counselling), together with a tight monitoring during the three trimesters and the post-partum period (to timely identify and treat possible obstetric complications or maternal disease flares), as well as the concept of multidisciplinary management, are currently milestones of the management of pregnancy in SLE patients. Nevertheless, the increasing knowledge on the compatibility of drugs with pregnancy has allowed a better treatment of these patients, by choosing medications that control maternal disease activity without harming the foetus. However, particular attention and strict monitoring should be dedicated to SLE pregnant women in particular clinical settings: patients with lupus nephritis and patients with aPL positivity or Antiphospholipid syndrome, who are at higher risk for maternal and foetal complications, but also patients with anti-Ro/SSA and/or anti-La/SSB antibodies, because of the risk of neonatal lupus. A discussion on family planning, as well as counselling on contraception, should be part of the everyday-practice for physicians caring for SLE women during their reproductive age. Another issue is the possible reduction of fertility in these women, that can be due to different reasons. Consequently, the request for assisted reproduction techniques has been increasing in the last years, so that rheumatologists and gynaecologists should be prepared to counsel SLE patients also in this particular setting.     

Chorea revealing systemic lupus erythematosus in a 13-year old boy: A case report and short review of the literature

Among the neurological manifestations of systemic lupus erythematosus (SLE), chorea is rare, presenting in less than 7% of the pediatric SLE patients. It can appear early in the onset of SLE, be the first or even the sole clinical feature of the illness and has strongly been associated with the presence of antiphospholipid antibodies. We report on the case of a 13-year old boy, admitted with acute onset chorea and finally diagnosed with SLE. Subsequently, we present a short review of the literature on the epidemiology, suggested pathogenesis, clinical presentation and treatment of this rare presentation of SLE.     

Childhood-onset systemic lupus erythematosus

OBJECTIVES: To describe the initial clinicolaboratory manifestations and short-term outcome in a series of Nigerian children with systemic lupus erythematosus (SLE). METHODS: A nonrandomized prospective study of consecutive cases of childhood-onset SLE. Baseline and follow-up clinicolaboratory data were collected and analyzed. Each patient was followed up for 12 months. RESULTS: Eleven children were studied. There were seven girls (F:M, 1.75). Mean ages at lupus onset and diagnosis were 10.0 +/- 2.53 years and 11.2 +/- 2.53 years, respectively. Mean time at onset of renal disease following SLE symptoms onset was 1.22 +/- 0.93 years. All cases were misdiagnosed prior to presentation; diagnosis was delayed in nine patients. Lupus activity was mild, moderate and severe in two, five and four patients, respectively. Hypertension (n = 5), nephrotic syndrome (n = 6), microerythrocyturia (n = 6) and acute renal failure (n = 7) were associated morbidities. Of the 27 presenting clinical features, 17 were nondiagnostic, while 10 were diagnostic. Fever (n = 9) was a major nondiagnostic symptom; major diagnostic manifestations were lupus nephritis (n = 11), arthritis (n = 10) and serositis (n = 7). Catastrophic antiphospholipid syndrome was diagnosed in three. The glomerular lesions were nonproliferative (n = 1), focal (n = 3) and diffuse (n = 7) proliferative lupus nephritis. Complete remission rate at end-point was 71.4%. Fourteen percent of the patients relapsed. Renal survival and mortality rates were 86.0% and 30.0%, respectively. CONCLUSION: In this study, severe renal and extrarenal comorbidities were common; mortality rate was also high. High frequency of misdiagnosis and delayed diagnosis were probably responsible for these.     

Elevated serum interleukin-15 levels in systemic lupus erythematosus.

Interleukin-15 (IL-15) has multiple biological properties, including the induction of other cytokine production and the inhibition of T cell apoptosis. Recently, IL-15 was reported to have a major role in synovial inflammation of rheumatoid arthritis, and that it provokes and amplifies the inflammatory process through the activation of TNF-alpha production. In systemic lupus erythematosus (SLE), the dysregulation of apoptosis and various cytokine production were observed and have been implicated in the pathogenesis of SLE. Thus, we tried to determine serum IL-15 levels in SLE patients and to assess the relationship among IL-15 levels, TNF-alpha levels and disease activity of SLE. Twenty SLE patients and 10 controls were studied. Paired serum samples were collected from all SLE patients at the time of presentation with active disease and at 4 weeks after institution of treatment. IL-15 levels were determined by ELISA and compared with the disease activity indices in SLE. The disease activity of SLE was measured using the SLE Disease Activity Index (SLEDAI) and laboratory parameters such as circulating immune complex (CIC), C3, C4, anti-DNA antibody, IgG, IgM, and IgA. The IL-15 levels in SLE patients were significantly higher than those of controls (5.38 +/- 4.89 vs. 1.04 +/- 1.26 pg/ml). However, elevated IL-15 levels did not correlate with the SLEDAI, nor did they correlate with other laboratory activity indices. The changes in serum IL-15 levels did not correlate with the changes in serum TNF-alpha in the disease course of SLE patients, whereas TNF-alpha reflected the changes in disease activity of SLE. Serum levels of IL-15 are elevated in SLE patients, but IL-15 did not correlate with the disease activity of SLE. TNF-alpha production in SLE patients was unlikely to be related with IL-15.     

Prognosis in systemic lupus erythematosus

Conclusions In SLE, morbidity is universal and fatality is significant. One cannot learn too much about the prognostic markers for this disorder. The identification by means of renal biopsy of subclasses of lupus nephritis spurred the development of new treatment regimens that have improved outcomes. While proliferative nephritis remains a marker of serious renal involvement, the newer indices that attempt to quantify the activity and chronicity of the renal lesion, as well as greater awareness of the importance of tubulointerstitial involvement and improvement in the amount of subendothelial electron-dense deposits with therapy, will likely permit further fine-tuning of the treatment of individual patients with lupus nephritis.Neuropsychiatric involvement in SLE is another major determinant of financial costs, morbidity and death. Unfortunately, our knowledge of the prognostic markers for this more heterogeneous group of manifestations is less advanced than for lupus renal involvement. Additional studies are needed urgently to determine the factors that predict the subsequent development of the different forms of neuropsychiatric lupus. The determinants will likely differ among the various forms of neuropsychiatric lupus, thereby permitting different preventative or treatment regimens to be developed.The role of social factors, particularly socioeconomic status, has attracted attention in the United States. The lessons are likely applicable elsewhere. Additional studies to identify social factors that can be modified may bring tangible benefits to SLE patients in this decade.Although not universally accepted, it does appear that as more SLE patients survive the acute disease, there is an inordinately high risk of developing vascular diseases, including coronary artery disease, stroke and peripheral vascular disease. As with neuropsychiatric lupus, the determinants may differ depending on the specific vascular disease. Better knowledge of these determinants will permit a further improvement in the overall prognosis for patients with SLE.     

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.     

Premature atherosclerotic disease in systemic lupus erythematosus--role of inflammatory mechanisms

Mounting evidence from a growing body of epidemiologic studies demonstrates that patients with systemic lupus erythematosus (SLE) are at increased risk for the development of premature cardiovascular disease (CVD). However, awareness of accelerated atherosclerosis in young SLE patients, albeit growing, is still limited, as documented by the brief case presented. Inflammation is thought to play an important role in both the pathogenesis of SLE, as well as atherosclerotic vascular disease. Inflammatory processes that are shared by SLE and atherosclerotic disease include immune complex deposition and fixation, autoantibody binding, complement activation and CD40-CD40 ligand interaction. By examining the inflammatory mechanisms in common between SLE and atherosclerotic disease, we can come to a better understanding of the pathophysiology of the accelerated atherosclerotic process seen in patients with SLE and can gain insights into developing and instituting preventative and treatment strategies. In this article, we present a case of a young woman with SLE who presents with chest pain, followed by a review of inflammation-based pathogenic mechanisms that are shared by SLE and atherosclerotic cardiovascular disease.     

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.     

Antinucleosome antibodies correlate with the disease severity in children with systemic lupus erythematosus

We compared the serum levels of antinucleosome antibodies (anti-NCS Abs) in thirty pediatric systemic lupus erythematosus (SLE) patients by using enzyme-linked immunosorbent assay (ELISA) to 29 adult SLE patients, 30 healthy controls, 21 juvenile idiopathic arthritis (JIA) and 23 Henoch-Schonlein purpura (HSP) patients as autoimmune disease controls. The mean anti-NCS Ab titer in the pediatric SLE patients was 1552.7+/-1842.2 U/ml, higher than those of adult SLE patients (194.3+/-402.7 U/ml), normal controls (9.5+/-5.7 U/ml) and disease controls (JIA: 7.7+/-4.0 U/ml, HSP: 5.7+/-4.4 U/ml) (p<0.05). The prevalence of both anti-NCS Ab (90%) and anti-ds DNA Ab (76.7%) in pediatric SLE patients were higher (p<0.05) than that of adult SLE patients (58.6% and 48.3%). A positive correlation was demonstrated between anti-NCS Ab and anti-dsDNA Ab as well as the SLEDAI scores in pediatric and adult patients (p<0.05). The inverse correlation of anti-NCS Ab levels with C3 was observed in both pediatric and adult SLE patients (pediatrics, r=-0.61, p=0.0003; adult, r=-0.44, p=0.02). Our data suggested that in pediatric SLE patients, anti-NCS Ab could be as good a marker for SLE diagnosis and disease activity assessment as in adult SLE patients.     

不同年龄发病的系统性红斑狼疮的临床特点

目的探讨不同年龄发病的系统性红斑狼疮的临床及免疫指标特点。方法回顾性分析108例不同年龄发病（老年发病48例,非老年发病60例）的系统性红斑狼疮的临床及实验室资料。结果非老年发病组抗dsD-NA抗体、Sm抗体、抗SSA、SSB的阳性率,血液系统、肾脏损害发生率显著高于老年发病组（P〈0.05）;老年发病组肌肉及关节受累发生率高于非老年发病组（P均〈0.01）。结论老年发病较非老年发病的SLE患者体内有更弱的自身免疫应答,病情侵袭性更低。