International Journal of Pediatrics
Volume 2019 (2019), Article ID 9537065, 7 pages
https://doi.org/10.1155/2019/9537065

Research Article

Unique Characteristics of Prepubertal Onset Systemic Lupus Erythematosus

R. Abdwani,¹ E. Abdalla,¹ and I. Al-Zakwani²

¹Pediatric Rheumatology Division, Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman
²Pharmacology and Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman

Correspondence should be addressed to R. Abdwani; rmabdwani@gmail.com

Received 2 April 2019; Accepted 20 May 2019; Published 27 May 2019

Academic Editor: Namik Y. Ozbek

Copyright © 2019 R. Abdwani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objectives. The aim of this study was to investigate the influence of age at disease onset on disease expression and outcomes of pediatric systemic lupus erythematosus SLE (pSLE). Methods. A total of 103 patients with pSLE from Sultan Qaboos University Hospital, Oman, were retrospectively studied. Epidemiological, clinical phenotype, disease severity, serology, treatment, and outcome were compared among the three groups using univariate statistical tests. Results. The mean disease duration of the cohort was 9.8 ± 4.7 years. The patients were divided into three groups: prepubertal onset (n=39) with mean age at diagnosis of 5.1 ± 2.0 years and pubertal disease onset (n=29) with mean age at diagnosis of 10.8 ± 1.0 years as well as postpubertal disease onset (n=35) group with mean age at diagnosis of 15.3 ± 1.6 years. The prepubertal pSLE cohort demonstrates unique characteristics with increased frequency of familial SLE (61%) of which 49% were from first-degree relatives. Similarly, this group had distinctive clinical features, which included increased renal disease in pubertal and postpubertal groups, respectively (51% vs 23% vs 20%; p=0.039). Prepubertal, similar to pubertal group, had a higher incidence of cutaneous manifestations than in the postpubertal group (74% vs 69% vs 46%; p=0.029). Laboratory features in prepubertal group were distinct with increased frequency of positive anti-cardiolipin antibodies (47%), anti-glycoprotein antibodies (42%), ANCA (62%), and low complement levels (97%) compared to pubertal and postpubertal group. The prepubertal group also has the lowest frequency of positive SSA antibodies (18%) and SSB antibodies (5.1%). The overall mean SLEDAI score in pSLE cohort was 15.6 ± 18.5. The mean SLEDAI scores among the groups showed no significance difference (p=0.110). The overall SLICC DI ≥1 was 36% with a mean damage score of 0.76 ± 1.38. No significant differences in damage index (SLICC DI ≥1) were noted among the groups. Conclusions. Distinct clinical features were identified in prepubertal onset pSLE population of Arab ethnicity. Given the high rate of consanguineous marriage and high frequency of familial SLE in this cohort, these manifestations could be explained by higher frequency of genetic factors that influence the disease pathogenesis.

1. Introduction

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease characterized by diverse clinical phenotype and course. Currently there are no known distinctive physiological or genetic pathways that can explain the variability in disease phenotypes. However, many factors have been postulated to contribute to the diversity of clinical phenotypes including race, ethnicity, and environmental and socioeconomic factors [1, 2].

Estimates of up to 20% of patients with SLE have the onset of disease before adulthood [3]. More accurate estimates are challenging due to lack of agreement on a clear age limits for the diagnosis of pediatric SLE (pSLE). While the most commonly used age at diagnosis to define pSLE is up to16 years, age ranges of 13 years to 18 years have been used as inclusion criteria for pSLE [3] depending on the practice of the country. In general, the diagnosis of SLE is rare <5 years and uncommon before adolescence [4, 5]. pSLE is in fact the same disease that occurs in adult onset SLE (aSLE); however, substantial differences have been reported [6–13]. Whether those differences are due to variations in biology or genetics has not been fully understood. pSLE has a higher disease severity at presentation, with higher prevalence of lupus nephritis, hematological manifestations, and central nervous system (CNS) involvement as well as constitutional symptoms than aSLE. Comparative studies of adults and children support that pSLE is more often treated with high doses of corticosteroids and immunosuppressive medications than aSLE. pSLE also has higher damage index in ocular, renal, and neuropsychiatric in domains than aSLE. Growth delay, osteoporosis, and negative impact on psychological and physical development, as well as poor treatment compliance, are other issues that need to be addressed in pSLE [6–13].

Previous studies within pSLE population suggest age of disease onset influences the expression of disease in terms of clinical presentation, disease activity, and outcome. Most of those studies were performed in European, Asian, and Latin American pSLE population [14–18]. There have been limited data on the relevance of age in Arab pSLE population. Therefore, the main objective of this study is to compare the effect of pubertal status on pSLE disease expression including clinical phenotype, laboratory findings, treatment, and outcomes among prepubertal, pubertal, and postpubertal onset pSLE cohort from Oman.

2. Methods

The medical records of patients with the diagnosis of SLE who were followed in the Rheumatology clinics at Sultan Qaboos University Hospital (SQUH) between 2007 and 2017 were reviewed. We included all patients with onset of SLE symptoms ≤18 years and fulfilled the1997 American College of Rheumatology (ACR) revised criteria [19]. Patients were excluded from the study if they did not satisfy any of the SLE classification criteria, had other autoimmune rheumatological disorders, or had missing data at disease onset and those that were lost to follow up at SQUH.

Patients were divided into three groups based on pubertal onset of disease. Puberty in boys is generally achieved between the ages of 9 and 14 years, while in girls it is generally achieved between the ages of 8 and 13 years. The three groups were divided accordingly: the prepubertal group included boys of age of ≤9 years and girls ≤8 years, the pubertal group included boys of age >9 and <14 years and girls >8 and <13 years, and the postpubertal group included boys of age ≥14 years and girls ≥13 years. The clinical, laboratory, treatment, and outcomes were compared among each group.

Demographic, clinical presentation and outcome data were retrospectively collected from the hospital electronic information system and analyzed. The demographic characteristics included age at disease onset, gender, disease duration, geographical origin (region of the country), family history of SLE, and degree of consanguinity. Clinical data collected included constitutional symptoms such as fever and weight loss; cutaneous manifestations (malar rash, photosensitivity, discoid rash, and other cutaneous vasculitis), mucosal involvement (oral or nasal ulcers), articular manifestation (arthritis), serositis (pleuritis and pericarditis) renal involvement (proteinuria >0.5 gm/day and cellular casts), central nervous system manifestations (seizures, psychosis, and headache), hematological involvement (leucopenia, lymphopenia, hemolytic anemia, and thrombocytopenia), cardiovascular manifestations (myocarditis, endocarditis, and hypertension), and pulmonary involvement (pneumonitis, shrinking lung syndrome, pulmonary hemorrhage, and pulmonary hypertension). Serological parameters were performed at our local institution including antinuclear antibodies (ANA), which were determined by indirect immunofluorescence using Hep-2 cells as substrate with a cut of >1:80; auto-antibodies including antidouble stranded DNA (anti-dsDNA), antiextractable nuclear antigen (anti-ENA) profile included anti-SSA/Ro, anti-SSB/La, anti-Smith, and anti-RNP, as well as antiphospholipid antibodies were measured qualitatively using enzyme linked immunosorbent assay (ELISA) technique. Auto-antibodies were considered positive if the value was above the cut-off for the laboratory at least in one determination during the follow-up period, except for anti-cardiolipin antibodies, which were considered present if there was two positive occasions, twelve weeks apart. Disease activity at disease onset was assessed using SLE disease activity index (SLEDAI) [20], while assessment of chronic cumulative organ damage was performed using Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index [21].

2.1. Statistical Analysis

Descriptive statistics were used to describe the data. For categorical variables, frequencies and percentages were reported. Differences between the SLE groups were analyzed using Pearson’s χ2 tests (or Fisher’s exact tests for expected cells <5). For continuous variables, mean and standard deviation were used to present the data while analyses were performed using ordinary least squares (OLS) regression. Survival analyses were analyzed using Kaplan-Meier estimates with differences examined utilizing log-rank test. An a priori two-tailed level of significance was set at 0.05. Statistical analyses were conducted using STATA version 13.1 (STATA Corporation, College Station, TX, USA).

3. Results

A total of 103 patients with mean disease duration of 9.8 ± 4.73 years were included in the study. The patients were divided into three groups: prepubertal onset (38%; n=39) with a mean age at diagnosis of 5.1 ± 2.0 years; pubertal disease onset (28%; n=29) with mean age at diagnosis of 10.8 ± 1.0 years; postpubertal disease onset (34%; n=35) with mean age at diagnosis of 15.3 ± 1.5 years. The demographic characteristics of the patients are described in Table 1. There were 83 (81%) females with an overall female (F):male (M) ratio of 4:1. However, significant differences in female to male ratio were noted across age groups. The F:M ratio increased with increasing age of disease onset from 2:1, 5:1 and 11:1 in prepubertal, pubertal, and postpubertal groups, respectively.

Table 1: Characteristics and outcomes of systemic lupus erythematosus (SLE) patients according to age at onset of disease.

Characteristic, n (%) unless specified otherwise
Pre-pubertal
Peri-pubertal
Post-pubertal
P-value

n=39
n=29
n=35

Age at disease onset (years)

Girls
≤ 8 (69%; n=27)
> 8 and <13
≥ 13(91%; n=32)
0.056

(83%; n=24)

Boys
≤ 9 (31%; n=12)
>9 and <14
≥14 (8.6%; n=3)

(17%; n=5)

Age, mean ± SD, years

<0.001

Sex ratio (F: M)
1: 2 (27:12)
1:5 (24:5)
1: 11 (32:3)
0.056

Region

<0.001

    Sharqiya
61%; n=24
24%; n=7
14%; n=5

    Batina
15%; n=6
24%; n=7
40%; n=14

    Muscat
5.1%; n=2
28%; n=8
29%; n=10

    Dhakhilia
5.1%; n=2
21%; n=6
11%; n=4

    Dhahira
0
3.4%; n=1
2.9%; n=1

    Dhofar
13%; n=5
0
0

    Musandam
0
0
2.9%; n=1

Family history of SLE
25 (64%)
9 (31%)
7 (20%)
<0.001

     degree
19 (49%)
4 (14%(
5 (14%)
0.001

DI ≥1
15 (39%)
12 (41%)
10 (29%)
0.520

Mortality
3 (7.7%)
1 (3.4%)
1 (2.9%)
0.626

SD: standard deviation; F: female; M: male; DI: damage index.

pSLE with prepubertal onset had unique characteristics with higher incidence of patients originating from Al-Sharqiya region of Oman (61%), with higher frequency of familial SLE (64%) of which 49% were from first-degree relatives. The postpubertal category of pSLE had higher incidence of disease in patients originating from Batinah region of Oman (40%) with lowest incidence of familial SLE (20%). However, the pubertal onset group had a more equal distribution of patients from various regions of Oman.

The most common clinical manifestation of pSLE overall cohort was arthritis (70%) followed by constitutional symptoms (66%), cutaneous manifestation (63%), nephritis (42%), and hematological manifestation (23%). Table 2 displays the clinical characteristics in each category. The prepubertal pSLE cohort demonstrates unique characteristics which included increased renal disease against pubertal and postpubertal groups, respectively (51% vs 23% vs 20%; p=0.039). Of the patients who had renal disease in prepubertal group (n=20), the majority had severe type of nephritis including class III nephritis (25%; n=5) and class IV nephritis (45%; n=9). Prepubertal, similar to pubertal group, had higher incidence of cutaneous manifestation than in postpubertal (74% vs 69% vs 46%; p=0.029). However, 51% of cutaneous manifestations in the prepubertal group were urticarial vasculitis, which is a distinguishing feature. In addition, prepubertal group has the lowest hematological involvement compared to the pubertal and postpubertal groups, respectively (28% vs 66% vs 71%; p<0.001)). In contrast, postpubertal group displayed the least cutaneous, renal, and pulmonary disease. Pubertal group showed no striking distinguishing features in the clinical presentation. The overall mean SLEDAI score in pSLE cohort was 15.6 ± 18.5. The mean SLEDAI score in each group showed no statistical significance difference, while overall SLICC disease index (DI) ≥1 was 36% with an overall mean damage score of 0.76 ± 1.38. No significant difference is SLICC DI ≥1 was noted among the groups as shown in Figure 1.

Table 2: Clinical manifestations of systemic lups erythematosus (SLE) patients according to age at onset of disease.

Characteristics
Pre-pubertal
Peri-pubertal
Post-pubertal
P-value

n (%)
n=39
n=29
n= 35

Cutaneous
74.4% (29)
69%(20)
45.7%(16)
0.029

UV (53.8%)
alopecia (27.6%)
alopecia (20%)

Nephritis
20 (51%)
10 (34%)
8 (23%)
0.039

Hematological
11 (28%)
19 (66%)
25 (71%)
<0.001

Arthritis
30 (77%)
19 (66%)
21 (60%)
0.281

Neurological
4 (10%)
6 (21%)
5 (14%)
0.500

Pulmonary
6 (15%)
4 (14%)
0
0.031

Serositis
8 (21%)
7 (24%)
3 (8.6%)
0.201

Constitutional symptoms
28 (72%)
21 (72%)
17 (49%)
0.063

SLEDAI (severe activity)
24 (61%)
18 (62%)
14 (40%)
0.110

SLDEDAI: Systemic Lupus Erythematosus Disease Activity Index.

Figure 1: Kaplan-Meir plot of time to damage (index ≥1) stratified by age at disease onset. No significant differences in time to damage index (≥1) were observed among the three SLE types (Plogrank=0.407).

Table 3 displays the immunological parameters of pSLE cohort. No significant differences were noted in the frequency of ANA and dsDNA in the different age groups. However, the prepubertal category demonstrates unique characteristics with increased frequency of positive anti-cardiolipin antibodies (47%), anti-glycoprotein antibodies (42%), ANCA (62%), and low complement levels (97%) compared to pubertal and postpubertal groups. The prepubertal group also has the lowest frequency of positive SSA antibodies (18%) and SSB antibodies (5.1%), while postpubertal group had the highest frequency of positive anti-smith antibody (40%). However, pubertal group does not demonstrate any striking laboratory features. The prescribed treatment for pSLE cohort at presentation and during disease course is described in Table 4. All groups were treated similarly with no significant differences noted in the use of corticosteroids or immununosuppressants such as azathioprine, mycophenolate, or cyclophosphamide. However, the postpubertal onset pSLE group was treated with rituximab in higher frequency than other groups.

Table 3: Investigations of systemic lups erythematosus (SLE) patients according to age at onset of disease.

Investigation type, n (%)
Pre-pubertal
Peri-pubertal
Post-pubertal
P-value

n=39
n=29
n=35

Anti smith
3 (7.7%)
7 (24%)
14 (40%)
0.003

Anti SSA
7 (18%)
12 (41%)
15 (43%)
0.040

Anti SSB
2 (5.1%)
5 (17%)
11 (31%)
0.004

Anti nucleosome
3 (7.7%)
5 (17%)
11 (37%)
0.011

Anti cardiolipin
17 (44%)
10 (34%)
5 (14%)
0.022

Anti glycoprotein
15 (38%)
8 (28%)
4 (11%)
0.025

ANCA
24 (62%)
11 (38%)
4 (11%)
<0.001

Low C3
38 (97%)
23 (79%)
27 (77%)
0.016

Percentage of antinucleosome among postpubertal is out of 30 as 5 were missing and not available.

Table 4: Medications of systemic lupus erythematosus (SLE) patients according to age at onset of disease.

Medications, n (%)
Pre-pubertal
Peri-pubertal
Post-pubertal
P-value

n=39
n=29
n=35

NSAIDS
20 (51%)
12 (41%)
11 (31%)
0.224

Hydroxychloroquin (HCQ))
38 (100%)
28 (97%)
34 (97%)
0.851

Prednisolone
39 (100%)
29 (100%)
28 (80%)
0.001

IVMP
20 (51%)
19 (66%)
27 (77%)
0.067

Azathioprine
27 (69%)
22 (76%)
24 (69%)
0.783

Methotrexate
10 (26%)
0
12 (34%)
0.001

Mycophenolate mofetil
25 (64%)
18 (62%)
25 (71%)
0.697

Cyclophosphamide
20 (51%)
15 (52%)
20 (57%)
0.861

Rituximab
6 (15%)
5 (17%)
15 (43%)
0.013

Immunoglobulin
3 (7.7%)
3 (10%)
7 (20%)
0.256

NSAIDs: nonsteroidal anti-inflammatory drugs; IVMP: intravenous methylprednisolone.

HCQ was missing in 1 patient under prepubertal.

4. Discussion

Studies comparing the influence of age on disease presentation and outcome in children with pSLE are scarce [14–18]. The main objective of this study was to investigate the impact of age of disease onset (prepubertal, pubertal, and postpubertal) within an Arab pSLE population on disease expression such as differences in clinical presentation, disease activity, serological findings, treatment, and outcomes. The main epidemiological difference between the groups was the F:M gender distribution. The postpubertal pSLE has the highest female predominance, which is 5.5 times higher than peripubertal group. There are many theories for the observed female predominance in SLE with growing age, including the influence of female sex hormones in disease pathogenesis most likely observed in postpubertal group. Despite the suggested relevance of hormonal factors in the etiology of SLE, a matched cohort study comparing prepubertal with pubertal cSLE demonstrated no important differences in disease features between groups irrespective of pubertal status [17]. Further investigations are needed to study the effects of the hormonal changes that occur during puberty in relations to the mechanisms leading to pSLE.

The prepubertal category has the highest frequency of familial SLE (64%) mainly from Al-Sharqiya region of Oman compared to 30% and 20% in pubertal and postpubertal group, respectively. The role of genetic factors may be relatively more important in the pathogenesis of prepubertal pSLE. In a recent Brazilian study, early onset pSLE (>6 years) patients were associated with complement (C1q, C4, and C2 deficiency) [22]. Recent research has shown that low total C4, C4A, and C4B gene copy number (GCN) were associated with a stronger risk for developing cSLE than adult SLE [22]. Unfortunately, complement function assay was not performed routinely on all the patients although this was strongly suspected as some patients had persistent hypocomplementemia (C3/C4) irrespective of disease activity. However, we identified DNASE1L3 mutation in a number of patients in the prepubertal group with unique clinical characteristics including a high disease activity with variable degree of renal involvement and urticarial vasculitis. Serologically, all patients presented with hypocomplementemia, while most also had positive anti-dsDNA and anti-neutrophil cytoplasmic antibodies [23].

Age of onset of pSLE affects the clinical manifestation of disease. Our study identified prepubertal onset of pSLE with distinct clinical features. Prepubertal onset pSLE had increased cutaneous manifestation and decreased hematological changes with increased tendency of renal disease, while postpubertal pSLE had decreased cutaneous and renal disease but increased hematological manifestations. Similarly, a large multicenter study, involving 847 children with pSLE divided into 3 similar groups, identified some distinct clinical and laboratory features in early onset and adolescent groups [16]. The mean SLEDAI score in our cohort, an index of disease activity at disease at onset, showed no statistical difference associated with early onset disease which is similar to other previous studies [16, 18]. However, in another study, infantile SLE were shown to have a more acute disease presentation with a higher disease activity index score (SLEDAI) than in prepubertal (2-10 years) and postpubertal (11-16 years) [14].

The overall damage index score demonstrated no significant difference is SLICC DI ≥ 1 as shown in the Kaplan-Meier estimates in our cohort (Figure 1). In the literature, other studies found no relation between the ages of pSLE onset and disease damage as measured by SDI [24, 25], while others showed high SLICC/ACR damage index and death associated with early onset SLE (<5 years) [26]. Our findings are different from the results of aSLE population for whom increasing ages are correlated with increasing damage score [27–29].

In our cohort, prepubertal onset pSLE had significantly higher frequency of positive ANCA, anti-cardiolipin antibody, anti-glycoprotein antibody, and higher frequency of lower complement levels. This group also displayed lower SSA, SSB, and antinucleosome antibodies, while postpubertal displayed higher anti-smith antibodies. Ethnic variations in the frequency of auto-antibodies with pSLE have been described previously [5, 17]. In two previous studies of Italian and Brazilian pSLE population, no significant differences in auto-antibody profile were identified between the three groups of pSLE population [15, 16]. The prepubertal group in our cohort displayed a higher frequency of familial SLE, in which DNASE1L3 gene mutation was identified in 13 patients who were tested and had characteristic features of early age of onset and positive ANCA [23]. Similarly, high frequency of positive anticardiolipin positivity may be explained by infectious process that may result in transient and nonpathogenic rise in antibody titer which may occur more commonly in younger children. In general, antiphospholipid antibody related thrombosis is rare in children and none of our patients developed any thrombotic events.

Comparative studies of adults and children support that pSLE is more often treated with high doses of corticosteroids and immunosuppressive medications than aSLE [15]. However, comparative studies within pSLE reveal no major difference in treatment frequencies and strategies according to various ages of onset groups [7, 9]. Similarly, our cohort of patients did not reveal significant differences. All patients were treated with prednisolone, hydroxychloroquine, and various immunosuppressive agents such as azathioprine, mycophenolate, and cyclophosphamide in comparable frequencies. However, rituximab was more frequently used in postpubertal group. Indications for using rituximab in the postpubertal group (n=19) were refractory lupus nephritis (63%), CNS vasculitis (13%), persistent arthritis (13%), autoimmune hemolytic anemia (6.3%), and mesenteric vasculitis (6.3%).

This study is not without limitations. One of the major limitations is the relatively small sample size. However, given the uncommon nature of illness, the sample size is considered reasonable to conduct the study. Furthermore, the retrospective nature of the study is another limitation. As the tanner staging was not included routinely in the medical records, we were not able to evaluate the effect of disease on pubertal delay as a reflection of damage index. Despite these limitations, we had no significant missing data to affect the findings of the study. Additionally, we had equal number of patients in each group, despite the rare occurrence of disease in children >5 years of age, to make the groups comparable. Finally, the cohort was a true representation of an Omani cohort of Arab ethnicity.

5. Conclusion

Our study demonstrates unique disease expression in prepubertal onset pSLE related to epidemiological, clinical, and laboratory features. Prepubertal onset pSLE had a higher frequency of familial SLE associated and lower F:M ratio than other groups. Clinically, prepubertal onset SLE had high renal and cutaneous manifestations of SLE. The laboratory features demonstrated higher anti-cardiolipin antibody, anti-glycoprotein antibody, anti-neutrophic cytoplasmic antibody, and lower complements than the other groups. Given the high rate of consanguineous marriage in Oman and a high frequency of familial SLE in this cohort (39.8%), these manifestations could be explained by a higher frequency of genetic factors that influence the disease pathogenesis [30]. Further genetic studies are warranted to identify additional genetic loci and to enhance our understanding of the pathogenesis of SLE.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Additional Points

There is sparse data emanating from Arab world on pediatric onset SLE. The authors believe that it would be important to share the results of their study as there is heterogeneity in disease epidemiology and presentation around the world. By sharing experiences, they would have better understanding of disease pathogenesis.

Ethical Approval

The authors would like to confirm that the protocol for the research project has been approved by Sultan Qaboos University, College of Medicine Ethics Committee.

Disclosure

The authors would like to confirm that the content has not been published or submitted for publication elsewhere.

Conflicts of Interest

The authors do not have any financial support or relationships that may pose conflicts of interest.

Authors’ Contributions

All authors contributed to the paper. All the authors of the manuscript have agreed to its content and are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with International Committee of Medical Journal Editors (ICMJE).

References

C. S. Lau, G. Yin, and M. Y. Mok, “Ethnic and geographical differences in systemic lupus erythematosus: an overview,” Lupus, vol. 15, no. 11, pp. 715–719, 2006.

N. Tiffin, A. Adeyemo, and I. Okpechi, “A diverse array of genetic factors contribute to the pathogenesis of systemic lupus erythematosus,” Orphanet Journal of Rare Diseases, vol. 8, no. 15, p. 2, 2013.

S. Kamphuis and E. D. Silverman, “Prevalence and burden of pediatric-onset systemic lupus erythematosus,” Nature Reviews Rheumatology, vol. 6, no. 9, pp. 538–546, 2010.

C. A. Silva, T. Avcin, and H. I. Brunner, “Taxonomy for systemic lupus erythematosus with onset before adulthood,” Arthritis Care & Research, vol. 64, no. 12, pp. 1787–1793, 2012.

R. Mina and H. I. Brunner, “Update on differences between childhood-onset and adult-onset systemic lupus erythematosus,” Arthritis Research & Therapy, vol. 15, no. 4, p. 218, 2013.

N. Ambrose, T. A. Morgan, J. Galloway, Y. Ionnoau, M. W. Beresford, and D. A. Isenberg, “Differences in disease phenotype and severity in SLE across age groups,” Lupus, vol. 25, no. 14, pp. 1542–1550, 2016.

T. A. Morgan, L. Watson, L. J. McCann, and M. W. Beresford, “Children and adolescents with SLE: not just little adults,” Lupus, vol. 22, no. 12, pp. 1309–1319, 2013.

R. Mina and H. I. Brunner, “Pediatric lupus—are there differences in presentation, genetics, response to therapy, and damage accrual compared with adult lupus?” Rheumatic Disease Clinics of North America, vol. 36, no. 1, pp. 53–80, 2011.

B. Amaral, G. Murphy, Y. Ioannou, and D. A. Isenberg, “A comparison of the outcome of adolescent and adult-onset systemic lupus erythematosus,” Rheumatology, vol. 53, no. 6, Article ID ket488, pp. 1130–1135, 2014.

H. I. Brunner, D. D. Gladman, D. Ibañez, M. D. Urowitz, and E. D. Silverman, “Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus,” Arthritis & Rheumatology, vol. 58, no. 2, pp. 556–562, 2008.

B. Livingston, A. Bonner, and J. Pope, “Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis,” Lupus, vol. 20, no. 13, pp. 1345–1355, 2011.

C. Malattia and A. Martini, “Paediatric-onset systemic lupus erythematosus,” Best Practice & Research Clinical Rheumatology, vol. 27, no. 3, pp. 351–362, 2013.

P. K. Bundhun, A. Kumari, and F. Huang, “Differences in clinical features observed between childhood-onset versus adult-onset systemic lupus erythematosus: a systematic review and meta-analysis,” Medicine (United States), vol. 96, Article ID e8086, 2017.

F. R. Pluchinotta, B. Schiavo, F. Vittadello, G. Martini, G. Perilongo, and F. Zulian, “Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes,” Lupus, vol. 16, no. 8, pp. 550–555, 2007.

E. Descloux, I. Durieu, P. Cochat et al., “Influence of age at disease onset in the outcome of paediatric systemic lupus erythematosus,” Rheumatology, vol. 48, no. 7, pp. 779–784, 2009.

R. C. Gomes, M. F. Silva, K. Kozu et al., “Features of 847 childhood-onset systemic lupus erythematosus patients in three age groups at diagnosis: A brazilian multicenter study,” Arthritis Care & Research, vol. 68, no. 11, pp. 1736–1741, 2016.

J. S. Hui-Yuen, L. F. Imundo, C. Avitabile, P. J. Kahn, A. H. Eichenfield, and D. M. Levy, “Early versus later onset childhood-onset systemic lupus erythematosus: Clinical features, treatment and outcome,” Lupus, vol. 20, no. 9, pp. 952–959, 2011.

L.-L. Chiang, Y.-T. Lin, H.-Y. Chan, and B.-L. Chiang, “Differential manifestations of prepubescent, pubescent and postpubescent pediatric patients with systemic lupus erythematosus: a retrospective study of 96 Chinese children and adolescents,” Pediatric Rheumatology, vol. 10, p. 12, 2012.

M. C. Hochberg, “Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus,” Arthritis & Rheumatology, vol. 15, no. 9, article 1725, 1997.

D. D. Gladman, Ibañez D., and M. B. Urowitz, “Systemic lupus erythematosus disease activity index 2000,” The Journal of Rheumatology, vol. 29, pp. 288–291, 2002.

D. Gladman, E. Ginzler, C. Goldsmith et al., “The development and initial validation of the systemic lupus international collaborating clinics/American college of rheumatology damage index for systemic lupus erythematosus,” Arthritis & Rheumatism, vol. 39, no. 3, pp. 363–369, 1996.

K. M. C. Pereira, A. G. A. Faria, B. L. Liphaus et al., “Low C4, C4A and C4B gene copy numbers are stronger risk factors for juvenile-onset than for adult-onset systemic lupus erythematosus,” Rheumatology, vol. 55, no. 5, pp. 869–873, 2016.

S. M. Al-Mayouf, A. Sunker, R. Abdwani et al., “Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus,” Nature Genetics, vol. 43, no. 12, pp. 1186–1188, 2011.

H. I. Brunner, E. D. Silverman, T. To, C. Bombardier, and B. M. Feldman, “Risk factors for damage in childhood-onset systemic lupus erythematosus: Cumulative disease activity and medication use predict disease damage,” Arthritis & Rheumatology, vol. 46, no. 2, pp. 436–444, 2002.

M. Bandeira, S. Buratti, M. Bartoli et al., “Relationship between damage accrual, disease flares and cumulative drug therapies in juvenile-onset systemic lupus erythematosus,” Lupus, vol. 15, no. 8, pp. 515–520, 2006.

S. M. Al-Mayouf and A. Al Sonbul, “Influence of gender and age of onset on the outcome in children with systemic lupus erythematosus,” Clinical Rheumatology, vol. 27, no. 9, pp. 1159–1162, 2008.

E. W. Karlson, L. H. Daltroy, R. A. Lew et al., “The relationship of socioeconomic status, race, and modifiable risk factors to outcomes in patients with systemic lupus erythematosus,” Arthritis & Rheumatism, vol. 40, no. 1, pp. 47–56, 1997.

A. Zonana-Nacach, A. Camargo-Coronel, P. Yáñez et al., “Measurement of damage in 210 Mexican patients with systemic lupus erythematosus: relationship with disease duration,” Lupus, vol. 7, no. 2, pp. 119–123, 1998.

N. Sutcliffe, A. E. Clarke, C. Gordon, V. Farewell, and D. A. Isenberg, “The association of socio-economic status, race, psychosocial factors and outcome in patients with systemic lupus erythematosus,” Rheumatology, vol. 38, no. 11, pp. 1130–1137, 1999.

M. M. Islam, “Consanguineous marriage in Oman: understanding the community awareness about congenital effects of and attitude towards consanguineous marriage,” Annals of Human Biology, vol. 44, no. 3, pp. 273–286, 2017.