Pediatric-onset Systemic Lupus Erythematosus Research Articles

Analysis of growth in female patients with pediatric-onset systemic lupus erythematosus

years, p<0.001). 90% of these patients showed period(s) of growth arrest, whereas 10% showed a gradual decline in growth only. The median height of the 36 patients with abnormal growth having reached age 16 years (presumed final height) was significantly lower compared to the height of patients diagnosed after 16 years (154.8 ±8.6 versus 161±6.1cm, p<0.001). Ethnicity, disease activity over time and cumulative medication use are currently being tested for their potential relation to growth impairment. Conclusion Growth was impaired in approximately half of female pSLE patients and may lead to abnormally low final height. Abnormal growth was characterized by periods of normal growth and growth arrest rather than gradual decline in growth, likely related to disease flares and/or treatment.

Association of Herpes Zoster Infection With Clinical Characteristics and MBL2 Gene Polymorphisms in Chinese Children With Systemic Lupus Erythematosus

In the first part of this study, we analyzed clinical factors associated with pediatric-onset systemic lupus erythematosus (SLE), and patient susceptibility to herpes zoster (HZ). In the second part of this study, we characterized MBL2 genotype polymorphisms in pediatric-onset SLE patients and their possible associations with HZ. This 10-year prospective cohort study compared pediatric-onset SLE patients from Taiwan with and without histories of HZ. By using 2 years as a standard interval, patients with early-onset and late-onset of HZ were compared. MBL2 gene polymorphisms in exon 1 at codon 54, and in the promoter at the position -221 and -550, were tested immediately after patient enrollment. We initially enrolled 98 SLE patients, and analyzed complete clinical characteristics of 82 patients (35 patients with HZ, 47 patients without HZ). The incidence of HZ was higher in SLE patients who had methylprednisolone pulse therapy, cyclophosphamide pulse therapy, and received higher cumulative steroid dose (P < 0.05 for all 3). There were no significant associations of HZ with MBL2 genotype or serum level of mannose-binding lectin. Pediatric-onset SLE patients were highly susceptible to HZ, with an incidence of 35.7%. Patients given steroid, cyclophosphamide, and high cumulative steroid dose were more likely to have had HZ. Deficiency of serum mannose-binding lectin and MBL2 gene polymorphism were not associated with HZ.

Worldwide incidence and prevalence of pediatric onset systemic lupus erythematosus

Compilation of worldwide data regarding the incidence and prevalence of pediatric-onset systemic lupus erythematosus (SLE) is needed in order to evaluate the scope of the disease in the pediatric population. A literature review was performed to unify the current data available on the global incidence and prevalence of pediatric-onset SLE. We examined 13 available epidemiological studies concentrated on the incidence and prevalence of pediatric-onset SLE. The available reports were predominantly from North America, Europe and Asia. The limited amount of studies available highlights the need for more epidemiological research in order to better comprehend the global scope of this disease.

Mannose-binding Lectin Expression Genotype in Pediatric-onset Systemic Lupus Erythematosus: Associations with Susceptibility to Renal Disease and Protection Against Infections

To study possible associations between extended mannose-binding lectin (MBL) expression genotypes and clinical manifestations and infections in children with systemic lupus erythematosus (SLE). Clinical and laboratory variables for a cohort of 125 patients with pediatric-onset SLE were obtained by clinical examinations and chart reviews. Controls were 137 age-matched and sex-matched healthy children and adolescents. MBL gene polymorphisms were genotyped by polymerase chain reaction. Serum MBL concentrations were measured by ELISA. The frequencies of extended MBL expression genotypes did not differ between patients and controls. There were 82 patients with SLE who had high MBL expression genotypes and 43 who had medium and low MBL expression genotypes. Patients with the high MBL expression genotype had renal disorders more frequently than patients in the group with medium and low MBL expression genotypes [54/82 (65.9%) vs 18/43 (41.9%), respectively; p = 0.013] and fewer serious bacterial infections [22/82 (26.8%) vs 20/43 (46.5%); p = 0.030]. Using logistic regression for patients with SLE, a high MBL expression genotype was independently associated with renal disorders (OR 2.49, 95% CI 1.15-5.39, p = 0.021) and had a protective effect against serious bacterial infections (OR 0.29, 95% CI 0.12-0.71, p = 0.007). MBL levels decreased significantly when patients with active SLE reached an inactive stage (1.56 ± 0.55 μg/ml vs 1.08 ± 0.65 μg/ml; p = 0.001), but these levels were still higher than those in controls. Our findings suggest that a high MBL expression genotype is a risk factor for renal disorder, while it has a protective effect against infections. Serum MBL levels reflect SLE activity.

Acute pancreatitis in pediatric and adult-onset systemic lupus erythematosus: A comparison and review of the literature

This study aimed to compare differences of acute pancreatitis between adult- and pediatric-onset systemic lupus erythematosus (SLE) patients and to clarify the risk factors for mortality. Medical records that carried the dual diagnosis of SLE and acute pancreatitis between 1991 and 2005 were reviewed. Forty-eight episodes of acute pancreatitis were identified in 13 pediatric-onset SLE (pSLE) and 27 adult-onset SLE (aSLE) patients. The prevalence was 1.34% overall, with higher prevalence in pSLE (5.22%) compared with aSLE (0.99%) (p < 0.001). The SLEDAI score on presentation of acute pancreatitis was higher in pSLE (mean ± SD: 21.77 ± 13.09) than in aSLE patients (13.37 ± 8.32) (p = 0.05). Eleven patients died during episodes of acute pancreatitis and mortality rate was significantly higher in pSLE than in the aSLE group (53.8% and 14.8%, respectively, p = 0.015). Mortality was associated with concurrent SLE symptoms (p = 0.049), higher SLEDAI score at presentation of acute pancreatitis (p = 0.011), severe acute pancreatitis (p < 0.001), and the presence of complications (p < 0.001). The multivariate logistic regression analysis showed that severity of acute pancreatitis was the most powerful risk factor for mortality in SLE patients with this disease. In summary, our results indicate that acute pancreatitis occurs more frequently, tends to be more severe, and is associated with higher mortality in pSLE patients when compared with aSLE patient.

Pediatric lupus in Asia

Of all patients with systemic lupus erythematosus (SLE), 15-20% are diagnosed during childhood, with disease onset prior to the age of 16 years. Because disease expression in SLE is influenced by environment factors and differs between racial and ethnic groups. The aims of this review were to describe prevalence, clinical manifestations, common infectious complications, and outcome of pediatric-onset SLE in Asia. The prevalence of pediatric-onset SLE was 6.3-19.3 per 100,000 in Asia. The ratio of female to male was 4.7-6.2. The mean age at diagnosis of pediatric-onset SLE was 8.6-13.5 years. The most common clinical features of pediatric-onset SLE in Asia were cutaneous rashes, arthritis, hematological involvement and nephritis. The occurrence of nephritis varies from 29% to 81%. The most common histopathology of lupus nephritis was diffuse proliferative glomerulonephritis (WHO Class-IV) which occurred in 39.4-54% of case of lupus nephritis. Pediatric-onset SLE patients with infections have poor outcomes than uninfected patients. Gram-negative bacilli are the most common microorganisms responsible for bacteremia in Asian patients with SLE. Recurrent major infections predict poorer disease outcome and associated organ damage in pediatric-onset SLE. Improving the survival of SLE patients was reported in Asia in recent decades. The survival was 92% at the age of 5 years, 86% at 10 years and 79% at 15 years in children with SLE in Taiwan in 2008.

Prevalence and burden of pediatric-onset systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease with a highly variable clinical course. Pediatric-onset SLE (pSLE) represents 10-20% of all SLE cases, and is associated with higher disease severity, including more-rapid damage accrual, than adult-onset SLE. As in adults, pSLE disease expression varies according to ethnicity, with a milder disease course in white patients. The majority of pSLE patients will have developed damage within 5-10 years of disease onset, most frequently involving the musculoskeletal, ocular, renal and neuropsychiatric systems. Owing to improvements in disease management and recognition over the past 20-30 years, patients now live longer, but as a result have increased disease damage. Premature atherosclerosis and osteoporosis have become increasingly prevalent morbidities in pSLE patients. Early atherosclerosis leads to a considerable rise in cardiovascular and cerebrovascular events, and failure to develop adequate peak bone mass during adolescence-a crucial period of bone accrual-is likely to lead to early osteoporosis and fractures. Patients with pSLE have an incurable, potentially devastating disease that occurs during a vulnerable period of psychosocial development, leading to specific and unique psychosocial stressors. Additional large, long-term follow-up studies in pSLE are needed to better understand the disease prognosis and to facilitate development of tailored treatments.

Complete complement deficiency in a large cohort of familial systemic lupus erythematosus

Genetic complete deficiency of the early complement components such as C1, C2 and C4 commonly results in a monogenetic form of systemic lupus erythematosus (SLE). However, previous studies have examined groups of complete complement deficient subjects for SLE, while a familial SLE cohort has not been studied for deficiencies of complement. Thus, we undertook the present study to determine the frequency of hereditary complete complement deficiencies among families with two or more SLE patients. All SLE patients from 544 such families had CH50 determined. Medical records were examined for past CH50 values. There were 66 individuals in whom all available CH50 values were zero. All but four of these had a SLE-affected relative with a non-zero CH50; thus, these families did not have monogenetic complement deficient related SLE. The four remaining SLE-affected subjects were in fact two sets of siblings in which three of the four SLE patients had onset of disease at <18 years of age. Both patients in one of these families had been determined to have C4 deficiency, while the other family had no clinical diagnosis of complement deficiency. In this second family, one of the SLE patients had had normal C4 and C3 values, indicating that either C1q or C2 deficiency was possible. Thus, only 2 of 544 SLE families had definite or possible complement deficiency; however, 1 of 7 families in which all SLE patients had pediatric onset and 2 of 85 families with at least 1 pediatric-onset SLE patent had complete complement deficiency. SLE is found commonly among families with hereditary complement deficiency but the reverse is not true. Complete complement deficiency is rare among families with two or more SLE patients, but is concentrated among families with onset of SLE prior to age 18.

Neuropsychiatric manifestations and antiphospholipid antibodies in pediatric onset lupus: 14 years of experience from a tertiary center of North India

The objective is to study the neuropsychiatric (NP) manifestations in pediatric onset systemic lupus erythematosus (SLE) at a tertiary care hospital of northwestern India applying American College of Rheumatology (ACR) case definitions in the context of occurrence of antiphospholipid antibodies (APLA). Data of 53 children with SLE were analyzed for NP syndromes. Tests for detection of APLA were performed as per international standards for quality control. Twenty-seven of the 53 (50.94%) children with lupus had at least one NP manifestation. The male to female ratio of our cohort of pediatric lupus was 1:2.8. However, there was significant male preponderance in patients with NPSLE as compared to patients without NPSLE (1:1.25 vs. 1:12; P < 0.0001). Majority of children with NPSLE (15/27, 55.5%) already had NP manifestations at the time of diagnosis and most of them (81.5%) had experienced more than one NP symptom. Headache was the commonest NP manifestation and was seen in 39.6% children with SLE followed by seizure disorder (35.8%) and cognitive dysfunction (16.9%). Tests for APLA were carried out in 37 of 53 (69.8%) patients with SLE and in 24 of 27 (88.8%) patients with NPSLE. While anticardiolipin antibodies were seen more frequently in children with NPSLE as compared to those without NPSLE (57.8 vs. 23%), lupus anticoagulant was more frequent in children without NPSLE (53.8 vs. 34.7%). However, these differences were statistically not significant. Eleven of the 27 children with NPSLE succumbed to their illness, primarily due to uncontrolled disease activity. Mean duration of follow-up of patients with NPSLE who are alive was 65.4 +/- 36.9 months. NP manifestations are common in pediatric onset lupus and contribute to significant morbidity. As compared to previously published literature, a significantly greater proportion of boys were affected. APLA were frequently detected in children with NPSLE. There is paucity of literature pertaining to NP manifestations of pediatric lupus in the context of APLA, especially with regard to antibodies to beta-2 glycoprotein I. To the best of our knowledge, this is the first detailed study on NP manifestations in childhood lupus from a developing country applying ACR case definitions.

Lack of association of mannose-binding lectin gene polymorphisms with development and clinical manifestations of systemic lupus erythematosus in Chinese children

Mannose-binding lectin (MBL) gene polymorphisms may be associated with adult-onset systemic lupus erythematosus (SLE), but studies in children with SLE are rare. This study tested the genetic association between MBL polymorphisms and paediatric-onset SLE in a cohort of Chinese children in Taiwan. In all 150 children with SLE and 100 healthy controls of comparable age were genotyped for codon 52, 54 and 57 mutations of the MBL gene using a polymerase chain reaction-based assay. Clinical manifestations, organ involvement, disease activity, laboratory characteristics and outcome were recorded and compared between patients with different MBL genotypes. Codon 54 mutation was fairly common in both SLE patients and controls, whereas codon 52 and codon 57 mutations were not detected in our study subjects. No statistically significant differences were found in allele frequencies of the codon 54 mutation between SLE and control groups. Moreover, no association was found between this MBL polymorphism and clinical manifestations, organ involvement, disease activity, laboratory characteristics or outcome of SLE. These results suggest that MBL polymorphisms do not influence susceptibility to paediatric-onset SLE and do not influence clinical manifestations of SLE in Chinese children.

Autoantibodies in Pediatric Systemic Lupus Erythematosus: Ethnic Grouping, Cluster Analysis, and Clinical Correlations

(1) To evaluate the spectrum of serum autoantibodies in pediatric-onset systemic lupus erythematosus (pSLE) with a focus on ethnic differences; (2) using cluster analysis, to identify patients with similar autoantibody patterns and to determine their clinical associations. A single-center cohort study of all patients with newly diagnosed pSLE seen over an 8-year period was performed. Ethnicity, clinical, and serological data were prospectively collected from 156/169 patients (92%). The frequencies of 10 selected autoantibodies among ethnic groups were compared. Cluster analysis identified groups of patients with similar autoantibody profiles. Associations of these groups with clinical and laboratory features of pSLE were examined. Among our 5 ethnic groups, there were differences only in the prevalence of anti-U1RNP and anti-Sm antibodies, which occurred more frequently in non-Caucasian patients (p < 0.0001, p < 0.01, respectively). Cluster analysis revealed 3 autoantibody clusters. Cluster 1 consisted of anti-dsDNA antibodies. Cluster 2 consisted of anti-dsDNA, antichromatin, antiribosomal P, anti-U1RNP, anti-Sm, anti-Ro and anti-La autoantibody. Cluster 3 consisted of anti-dsDNA, anti-RNP, and anti-Sm autoantibody. The highest proportion of Caucasians was in cluster 1 (p < 0.05), which was characterized by a mild disease with infrequent major organ involvement compared to cluster 2, which had the highest frequency of nephritis, renal failure, serositis, and hemolytic anemia, or cluster 3, which was characterized by frequent neuropsychiatric disease and nephritis. We observed ethnic differences in autoantibody profiles in pSLE. Autoantibodies tended to cluster together and these clusters were associated with different clinical courses.

Paediatric systemic lupus erythematosus: prognostic impact of antiphospholipid antibodies

The aim of our study was to investigate the prognostic impact of aPL in paediatric onset systemic lupus erythematosus (p-SLE). This retrospective study included 56 patients with p-SLE. Chi2-test, Fisher's exact test, incidence rate ratio and Kaplan-Meier survival curves were used to compare aPL-positive and aPL-negative patients considering the value of SDI (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for SLE) at the end of follow-up, the occurrence of thromboses, organ system involvements and need for immunosuppressive treatment in addition to corticosteroids. Anti-cardiolipin antibodies and lupus anticoagulants were detected in 27 (49%) and 19 (35%) patients, respectively. These aPL were frequently transient or intermittent (10 and 15 cases, respectively), and only rarely persistent over time (five cases). The risk of thrombosis was significantly higher (odds ratio = 6.42) and occurred earlier in the presence of aPL, especially if aPL were persistent (P < 0.05). The association between aPL and neurological, renal, haematological manifestations or need for immunosuppressive treatment was not statistically significant. After a mean follow-up of 7.2 yrs, 30 patients (54.5%) had an SDI score > or = 1. The risk of damage (SDI > or = 1) in aPL-positive patients was three times higher than in aPL-negative patients (P < 0.05). Four of the six fatal cases occurred in the aPL-positive group. The presence of aPL in p-SLE could represent not only a risk factor for thrombosis but also a poor prognostic factor overall.

Mizoribine intermittent pulse protocol for induction therapy for systemic lupus erythematosus in children: an open-label pilot study with five newly diagnosed patients

The objective of the current work is to report our preliminary experience with the mizoribine (MZR) intermittent pulse protocol for induction therapy for newly diagnosed pediatric-onset systemic lupus erythematosus (SLE). Five consecutive patients who were newly diagnosed as having SLE with biopsy-proven lupus nephritis were recruited for an open-label trial of prednisolone (PDN) and MZR intermittent pulse therapy (10 mg/kg for 2 days of the week for 12 months). Data on the renal response and serologic lupus activity were collected prospectively. The baseline characteristics of the patients were: mean age, 11 years; urinary protein/creatinine ratio (U-prot./cre.), 0.99 +/- 0.91; serum complement hemolytic activity (CH50), 10.6 +/- 1.3 (normal, 23-46 U/ml); serum anti-dsDNA antibody titer, 258.6 +/- 125.5 IU/ml (normal, <12.0 IU/ml); serum creatinine, 0.5 +/- 0.1 mg/dl; European Consensus Lupus Activity Measurement index (ECLAM), 7.4 +/- 1.1. The primary endpoint was the interval until the development of a flare of SLE. Despite gradual tapering of the PDN dose, significant improvement as compared to the baseline values was observed in all the parameters examined at 3, 6, and 12 months of treatment. After 12 months therapy, complete response was achieved in all of the patients, except for 1 patient who showed poor drug compliance. In two patients who had severe lupus nephritis at the first renal biopsy, marked histologic improvement was confirmed at the second renal biopsy. No serious adverse effects were observed. We believe that the MZR pulse protocol combined with PDN for induction therapy may be the treatment of choice in selected young patients with SLE. Further studies to confirm the long-term efficacy and safety of our current protocol in larger numbers of patients are, however, needed.

Association of Cumulative Cyclosporine Dose with Its Irreversible Nephrotoxicity in Japanese Patients with Pediatric-Onset Autoimmune Diseases

Cyclosporine (CsA)-induced nephrotoxicity can become a major obstacle to continuous use. The aim of this study was to optimize CsA dose to avoid its irreversible nephrotoxicity. Twenty-three Japanese patients with pediatric-onset systemic lupus erythematosus or idiopathic nephrotic syndrome, who were maintained in a stable condition by oral dosing of CsA microemulsion, were enrolled in this study. The patients were stratified into 3 groups; those with no, reversible, and irreversible nephrotoxicity, according to periodically performed renal pathohistological examinations. A higher concentration of CsA in blood (p=0.002-0.011) and a longer duration of CsA treatment (p=0.002) were risk factors for irreversible nephrotoxicity, and the cumulative CsA dose, the product of the maintenance dose and duration of CsA treatment, was predictive of nephrotoxicity (p=0.036). The maximum target blood concentration at 2 h post-dose, C(2), to avoid CsA-induced irreversible nephrotoxicity was 700 ng/ml, although the cumulative CsA dose of 4850 mg/kg would result in a 50% probability of nephrotoxicity.

An altered immune response to Epstein‐Barr nuclear antigen 1 in pediatric systemic lupus erythematosus

New examples support the concept that host immune responses to pathogenic organisms can act as the nidus for autoimmunity. Two such examples implicate the Epstein-Barr virus (EBV) in systemic lupus erythematosus (SLE), i.e., data consistent with SLE anti-Sm and anti-60-kd Ro autoantibodies emerging from distinct humoral immune responses to Epstein-Barr nuclear antigen 1 (EBNA-1). We undertook this study to further test whether the humoral immune response to EBNA-1 is a risk factor for pediatric SLE. Sera from pediatric lupus patients and healthy matched controls were tested for anti-EBNA-1 by Western blotting and enzyme-linked immunosorbent assay (ELISA). To define the fine specificity of their anti-EBNA-1 humoral immune response, fragments of EBNA-1 and the maximally overlapping unique octapeptides of EBNA-1 were tested by modified ELISAs. All 36 pediatric SLE patient sera tested recognized EBNA-1, while sera from only 25 of 36 matched EBV-positive controls targeted EBNA-1 (P < 0.005). Epitope mapping revealed that the humoral anti-EBNA-1 response in pediatric SLE was distinct from and less restricted than that in matched normal individuals. Meanwhile, no significant differences between SLE patient sera and control sera were observed in the responses to other herpesviruses or in binding to sequential epitopes from cytomegalovirus immediate-early antigen or EBNA-2. Anti-EBNA-1 antibodies are associated with pediatric-onset SLE. Furthermore, an altered humoral immune response to EBNA-1, characteristic of SLE, has been found and may be an important SLE susceptibility factor.

Assessment of atherosclerotic risk factors and endothelial function in children and young adults with pediatric-onset systemic lupus erythematosus.

To characterize atherosclerotic risk factors and endothelial function in pediatric-onset systemic lupus erythematosus (SLE). Lipoproteins, oxidized state, and autoantibodies to oxidized low-density lipoprotein (Ox-LDL) were assessed. Endothelial function was evaluated using brachial artery reactivity. Thirty-three SLE patients and 30 controls were studied. SLE subjects had significantly decreased mean high-density lipoprotein (HDL) cholesterol (41 mg/dl versus 51 mg/dl; P = 0.002) and apolipoprotein A-I (97 mg/dl versus 199 mg/dl; P = 0.0004). There was no difference between groups in markers of oxidized state (including nitric oxide metabolites, isoprostanes, and Ox-LDL) or in endothelial function. However, SLE subjects had increased median anti-Ox-LDL IgG (2,480 relative light units [RLU] versus 1,567 RLU; P = 0.0007) and IgG immune complexes with LDL (4,222 RLU versus 2,868 RLU; P = 0.002). Pediatric SLE patients had significantly decreased levels of HDL cholesterol and apolipoprotein A-I and elevated titers of autoantibodies to Ox-LDL. Despite these atherosclerotic risk factors, SLE patients had normal measures of oxidized state and endothelial function.

Methotrexate therapy in systemic lupus erythematosus.

There are 12 non-controlled and only two controlled studies using methotrexate (MTX) in a total of 207 SLE patients in the literature. The majority of these studies evaluated mainly cutaneous and/or articular involvement and attained good results. Two studies evaluated a small number of patients with lupus nephritis, achieving discordant results. Two other studies in pediatric onset systemic lupus erythematosus (SLE) also presented conflicting results, it being relevant that the one with poor response had the majority of patients with nephritis. One of the controlled trials was retrospective and concluded that MTX was effective in the treatment of antimalarial-resistant lupus arthritis and that toxicity leading to discontinuation of MTX was infrequent. The other controlled study was a double-blind, randomized, placebo-controlled clinical trial that evaluated SLE patients with mild activity. The authors concluded that MTX was effective in controlling cutaneous and articular activity and permitted prednisone dose reduction. The side effects were frequent but only 10% of patients needed to discontinue the medication. The accumulative evidence suggests that MTX in a low weekly dose may be effective in SLE patients with articular and/or cutaneous involvement with no response to antimalarials and low-dose prednisone and in patients in whom we can not reduce prednisone dose due to articular or cutaneous activity. Caution is required concerning the side effects.