Demographic Presentation, Activity Indices, Damage Index: Comparative Study Between Pediatric Lupus Erythematosus Versus Adult Systemic Lupus Erythematosus in Sample Egyptian Population

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that can affect all organ systems due to alterations of both the innate and adaptive immune systems. Although onset during infancy is rare, the incidence of SLE rises steadily during childhood until mid-adulthood, especially among females. In this study we aimed to highlight the possible discrepancies in clinical presentations as well as serological profiles of pediatric and adult onset SLE patients, we also focused attention on the disease assessment by SLE activity index (SLE DDI) and damage index at time of presentation. Subjects were subdivided into 2 groups: Group I: A total of 92 Pediatric systemic lupus erythematosus (pSLE) that were selected from the students attending the school children hospital of medical health insurance. Group II: A total of 90 adult systemic lupus erythematosus (aSLE) patients and were recruited from those attending the Alexandria Main University Hospital and outpatient clinic. All patients were subjected to: detailed history taking and complete physical and mental examination, also activity indices as well as damage index were applied for every lupus patient of the studied groups, laboratory investigations were done for all patients. Our results demonstrated that, regarding mucocutaneous manifestations: pSLE patients have values higher than aSLE patients regarding photosensitivity (63.3% and 61.1%) and vascular lesions (23.9% and 22.2%) respectively. Regarding haematological manifestations: pSLE patients have values higher than aSLE patients regarding anemia (86.96% and 84.4), leucopenia (28.3% and 22.22) and thrombocytopenia (46.7% and 25.56%) respectively. Regarding renal abnormalities, pSLE patients have higher incidence of nephritic syndrome than aSLE patients. Regarding SLEDAI, pSLE patients have values statistically higher than aSLE patients. Regarding SLAM, pSLE patients have values statistically higher than aSLE patients, while no differences of damage index was noticed.


Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems triggered by the production of auto antibodies. [1] SLE presents throughout the age spectrum. An estimated 10-20% of patients experience the onset of SLE prior to adulthood. More precise estimates are difficult due to a lack of a clear age limit for diagnosis of pediatric SLE. The maximum age at diagnosis most commonly used to define pediatric SLE is 16 years but ages ranged from 14-20 years in various studies. [2,3] Although there are limited studies directly comparing adult and childhood onset SLE, it has been suggested that pediatric lupus patients have a more aggressive disease course and an increased rate of more unusual clinical presentations compared with their adult counterparts. [4] Delay in SLE diagnosis is associated with higher mortality and a reduced likelihood of achieving remission. [5]. In adult with SLE remission for 1-years is required in as many as 6.5% of the patients conversely, despite a lack of firm estimates, remission is exceedingly rare in pediatric SLE. [6] Comparisons of relatively small pediatric and adult cohorts of SLE patients have shown that children and adolescents have more active lupus, in particular lupus nephritis, at presentation and over time than adults. Compared to adults with lupus, children receive more intensive drug therapy and accrue more end-organ damage, often related to steroid toxicity [2]. In the Lupus in Minorities: Nature vs. nurture (LUMINA) multiethnic cohort, young age was an important independent predictor of new or worsening proteinuria on routine screening, and adolescent onset of SLE resulted in more aggressive disease and worse outcomes. [7,8] The high morbidity and mortality observed from lupus nephritis in past studies of SLE in children may be due to delays in diagnosis and treatment [1,3,4].
Major cause of death in pediatric SLE and adult SLE include renal disease, severe disease flares, and infections. [7] New psychiatric lupus is a risk factors of poor outcome in pediatric SLE, cardiovascular disease remains on important cause of death in a SLE.
There is a controversy as to whether age at SLE onset constitutes a risk factors for poor outcome. [8] Despite improved survival rates in SLE patients of all age, there remains substantial morbidity due to disease damage. [7] In a SLE, increasing age and larger duration of disease are correlated with disease damage. [8]. There is a trend towards higher rates of any disease damage in adolescent-onset SLE patients. [6] In this study we aimed to highlight the possible discrepancies in clinical presentations as well as serological profiles of pediatric and adult onset SLE patients, we also focused attention on the disease assessment by SLE activity index (SLE DDI) and damage index at time of presentation.

Subject and Methods
This is a comparative study conducted between December 2013 till December 2015, included 182 patients fulfilling the systemic lupus international collaborating clinics (SLICC) 2012 criteria for diagnosis of SLE [9], patients were subdivided into 2 groups: Group I: A total of 92 Pediatric systemic lupus erythematosus (pSLE) patients that were selected from inpatients and outpatietns clinic of students attending the sporting school children hospital of medical health insurance.
Group II: A total of 90 adult systemic lupus erythematosus (aSLE) patients that were recruited from those attending the Alexandria Main University Hospital and outpatient clinic.

All Patients Were Subjected to
I. Detailed history taking and complete physical and mental examination. II. Clinical assessment of activity including: i. SLE Disease Activity Index (SLEDAI): [10] Minimum score is 0 and maximum is 105. (score less than 4 as inactive, from 4 to 8 as mild, from 9 to 12 as moderate and score more than 12 as having severe disease activity). ii. Systemic lupus activity measure (SLAM). [11].
Which include subjective features reported by the patients, the higher the number, the more active the disease. iii. Damage Index (SLEDDI): [12] Maximum possible score is 47. III. Laboratory investigations done for the studied group of patients included: i. Complete blood picture, ii. liver enzymes (ALT, AST), iii. renal function test (blood urea, serum creatinine, creatinine clearance and 24 hour urine proteins and urinary albumin creatine ratio). iv. complete urine analysis, v. erythrocyte sedimentation rate (ESR), vi. C-reactive protein (CRP), vii. C3, C4, viii. lipid profile including serum cholesterol, triglycerides, ix. antinuclear antibodies (ANA) titre.

Statistical Analysis of the Data
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. Comparison between different groups regarding categorical variables was tested using Chi-square test. Normally quantitative data was compared using student t-test, or F test (ANOVA), abnormally distributed data was compared using Mann Whitney test or Kruskal Wallis test, Correlations between two quantitative variables were assessed using Pearson or Spearman coefficient according to test of normality. Significance of the obtained results was judged at the level of 0.05.

Routine Investigations
Routine investigations of the studied patients were presented in table (4) Blood urea (mg/dl) Blood urea ranged from 7-67 and 11-78 with the mean of 32.1±20.6 and 36.5±16.8 for pSLE patients and aSLE patients respectively with no statistical significant differences between the two studied groups (P=0.221).
Serum creatinine (mg/dl) Serum creatinine ranged from 0.4-4.1 and 0.94-4.96 with the mean of 2.01±1.33 and 2.69±2.01 for pSLE patients and aSLE patients respectively with no statistical significant differences between the two studied groups (P=0.369).
Creatinine clearance (ml/min) Creatinine clearance ranged from 22-89 and 20.2-90.0 with the mean of 62.1±21.4 and 52.6±24.3 for pSLE patients and aSLE patients respectively with no statistical significant differences between the two studied groups (P=0.221).
ALT (U/L) ALT ranged from 10-305 and 15-322 with the mean of 45.2±50.2 and 56.9±45.8 for pSLE patients and aSLE patients respectively with no statistical significant differences between the two studied groups (P=0.098). Study Between Pediatric Lupus Erythematosus Versus Adult Systemic Lupus Erythematosus in Sample Egyptian Population AST (U/L) AST ranged from 10-230 and 29.5-310.0 with the mean of 43.7±39.6 and 58.0±42.1 for pSLE patients and aSLE patients respectively with no statistical significant differences between the two studied groups (P=0.211).
ESR ESR ranged from 12-110 and 5-120 with the mean of 47.33±33 and 61.33±27.11 for pSLE patients and aSLE patients respectively with statistical significant differences between the two studied groups (P=0.016).
Urinary Alb/creatinine ratio It ranged from 22-105 and 20-122 with the mean of 61.3±28.7 and 70.8±30.1 for pSLE patients and aSLE patients respectively with statistical significant differences between the two studied groups (P=0.041).
CRP Positive CRP were found in 3 and 7, while negative CRP were found in 89 and 83 patients for pSLE patients and aSLE patients respectively, with no statistical significant differences. (P=0.0980).  SLEDDI ranged from 0-7 and 1-8 with the mean of 1.5±2.1 and 2.33±2.07 for pSLE patients and aSLE patients respectively, there were no statistical significant differences between the two studied groups regarding SLEDDI (P=0.074).

Disease Activity
C3 (g/L) ranged from 0.02-1.79 and 0.11-1.98 with the mean of 0.57±0.42 and 0.71±0.51 for pSLE patients and group aSLE patients respectively, there were no statistical significant differences between the two studied groups regarding C3 (P=0.254) C4 (g/L) ranged from 0.20-0.92 and 0.32-1.01 with the mean of 0.34±0.31 and 0.44±0.54 for pSLE patients and group aSLE patients respectively, there were no statistical significant differences between the two studied groups regarding C4 (P=0.211) Anti-ds DNA (Iu/L) ranged from 30-396 and 25-421 with the mean of 78.6±42.6 and 112.9±51.6 for pSLE patients and aSLE patients respectively, pSLE patients have statistically higher values than aSLE patients. (P=0.038).

Discussion
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that can affect all organ systems due to alterations of both the innate and adaptive immune systems. Although onset during infancy is rare, the incidence of SLE rises steadily during childhood until mid-adulthood, especially among females. [13] Our study focused on comparing the similarities and differences between pediatric and adult onset systemic lupus erythematosis, as well as estimating the activity indices and damage index at the time of study.
The female to male ratio in adult onset SLE is generally found to be slightly more than 10: 1. A higher proportion of men is often reported in childhood onset SLE in some series. [14] In our study, men represented 9% of the studied pediatric onset SLE with a female to male ratio similar to that in the adult onset SLE.
Comparison of the clinical features at onset between childhood onset and adult onset patients reveals both similarities and important differences. The frequency of skin, joint, serositis, and haematological affection were similar in both groups and correlate with previous reports. However, pediatric onset SLE patients showed increased incidence of renal involvement, fever, and lymphadenopathy, which had been reported by other authors. [15] In the presence of suggestive clinical signs and symptoms, in agreement with our study, laboratory testing can support and confirm the diagnosis of SLE. A hallmark of SLE is the production of multiple autoantibodies. The commonest autoantibody is the antinuclear antibody (ANA), present in more than 95% of pSLE patients. In the presence of an ANA, it is appropriate to examine for specific autoantibodies including double-stranded DNA (dsDNA) and the extractable nuclear antigens(ENAs), recognizing that particular autoantibodies correlate with certain disease features. [16] The test for ANA has high sensitivity (>95%), but its specificity for SLE is as low as 36%. [17] Moreover, up to 10% of 'healthy' children will demonstrate a positive ANA. In SLE, anti-dsDNA antibodies have high specificity. Anti-Smith antibodies (anti-Sm, not to be confused with anti-smooth muscle antibodies indicative of autoimmune hepatitis) have the greatest specificity but low sensitivity for SLE. Both anti-ds-DNA and anti-Sm antibodies are associated with renal involvement, and anti-Sm may be associated with more severe disease. Other autoantibodies observed in pSLE include antiribonuclear protein (anti-RNP), anti-Ro (also known as anti-SSA) and anti-La (or anti-SSB) antibodies. Offspring of females with anti-Ro antibodies are at risk for Neonatal Lupus Erythemathosus (NLE). NLE can lead to congenital heart block in these neonates, therefore, any adolescent female with pSLE and anti-Ro antibodies should be informed of this risk prior to any pregnancy, and referred for fetal echocardiogram monitoring by the end of the first trimester. Other supporting features for SLE include hypocomplementemia (particularly C3 and C4 which are readily testable), cytopenia of one or more cell line as discussed earlier, and elevated ESR in the face of a normal C-reactive protein (CRP). Interestingly, CRP is often normal or only minimally elevated during a SLE flare, except when the flare is of serositis, or in the presence of concurrent infection or macrophage activation syndrome.
Our study showed that, noticeable elevations in liver enzymes, the mean of ALT were 45.2±50.2 and 56.9±45.8 and the mean of AST were 43.7±39.6 and 58.0±42.1 for pSLE and aSLE patients respectively with no statistical significant differences.
Elevated liver enzymes can indicate fatty liver (secondary to corticosteroids), an adverse drug reaction or active SLE. Less common causes in pSLE would include an intrahepatic thrombotic process, or elevated transaminases as a reflection of muscle inflammation. [17] Routine hematology and biochemistry tests are used to monitor disease status for flare and remission, medication side effects, and the effects of chronic disease and inflammation. Urine analysis should be done regularly for proteinuria, hematuria, and to examine for casts, while urine protein to creatinine ratios (spot, or 24 hour collection) are required for monitoring response to treatment of lupus nephritis. [18] In agreement with our study, Tarr, et al., (2015) compare the clinical course of adult and pediatric-onset SLE. Data from 342 adult patients and 79 children were analyzed using hospital medical records. Organ manifestations, laboratory parameters, and immunoserological characteristics were evaluated. They found that, gender distribution was not significantly different between both groups with disease starting in childhood vs adulthood. The prevalence of the following manifestations was significantly higher for pediatric than for adult-onset disease including: lupus nephritis (43% pediatric vs 26.4% for adult-onset), hematological disorders (57% vs 36.4%), photosensitivity (20% vs 9%), and mucosal ulceration (11.4% vs 4%). For adult-onset SLE, neurological symptoms (30% vs 6%). While this study disagreement with our study regarding polyarthritis (86% vs 68%) occurred significantly more frequently than in children. [19]

Conclusions
From our study we concluded that, both the clinical manifestations as well as serological characteristic of pediatric and adult onset SLE in Egyptian population is quite different. Pediatric onset SLE is a life long autoimmune disease that may be difficult to diagnose due to the heterogenicity of clinical presentations. It tends to lead a more active and aggressive disease course than adult onset SLE resulting in greater disease damage, increase in morbidity and mortality rates. The value of this study is to determine the long term outcome of early onset systemic lupus in addition to adopt a better tailored management, follow up and treatment approach for such young lupus patients.