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ORIGINAL ARTICLE
Ahead of print publication  

Systemic lupus erythematosus organ manifestation and disease activity in children based on Mexican systemic lupus erythematosus disease activity index score at East Java, Indonesia


1 Medical Doctoral Program Student, Faculty of Medicine, Universitas Airlangga, Surabaya; Department of Child Health, Dr Soetomo General Academic Hospital-Faculty of Medicine Airlangga University, East Java, Indonesia
2 Department of Child Health, Dr Soetomo General Academic Hospital-Faculty of Medicine Airlangga University, East Java, Indonesia

Date of Submission23-Apr-2021
Date of Acceptance27-Sep-2021
Date of Web Publication27-Nov-2021

Correspondence Address:
Zahrah Hikmah,
Medical Doctoral Program Student, Faculty of Medicine, Universitas Airlangga,Surabaya, Surabaya 60131, East Java
Indonesia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_76_21

  Abstract 


Background: Disease activity in systemic lupus erythematosus (SLE) is associated with organ damage, outcome worsening, comorbidities, and mortalities in the patients. This study aimed to investigate the organ manifestation of juvenile SLE (jSLE) onset and the correlation of organ manifestation with disease activity according to the Mexican SLEs disease activity index scores.
Materials and Methods: This was a cross-sectional retrospective study and was conducted at Dr. Soetomo Academic Hospital, Indonesia. The study enrolled 62 subjects with complete medical records, divided into active jSLE (39 subjects) and inactive jSLE (23 subjects). The mean age of all subjects was 11.09 years, with a male/female ratio of 1:3.9. We analyzed the patient's characteristics, laboratory results, and organ manifestations using paired sample t-test, Fischer's Exact Test, and Mann–Whitney U-Test. The correlation between organ manifestation and disease activity was analyzed using Spearman's rho correlation. The odds ratio was analyzed using Mantel-Haenszel Common Odds Ratio Estimation.
Results: Malnutrition is still high in jSLE, affecting 45.16% of all subjects. Malar rash (69.23 vs. 41.67%) and bicytopenia (41.03 vs. 12.50%) were significantly higher in active jSLE than inactive. The renal manifestation was correlated with active jSLE than other organ manifestations. Renal has a 19.714-fold higher risk in active jSLE. It had been found that skin and hematological manifestations are the most typical organ manifestations.
Conclusions: The renal manifestation was strongly correlated with disease activity and had the highest risk in active jSLE.

Keywords: Juvenile-onset of systemic lupus erythematosus, malnutrition, Mexican-systemic lupus erythematosus disease activity index, renal manifestation



How to cite this URL:
Hikmah Z, Endaryanto A, Gede Ugrasena I D. Systemic lupus erythematosus organ manifestation and disease activity in children based on Mexican systemic lupus erythematosus disease activity index score at East Java, Indonesia. Indian J Rheumatol [Epub ahead of print] [cited 2022 Jan 16]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=331346




  Introduction Top


Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a heterogeneous presentation.[1] The onset during childhood or before the age of 16 years was approximately 10%–20% of all cases[2] with the females as the predominant subjects.[3] The juvenile-onset of SLE (jSLE) is a rare disease. It happens to 0.3–0.9/100,000 children per year, and the prevalence is 3.3–8.8/100,000 children.[4] jSLE usually has more aggressive and worse outcomes than adult-onset with several organ manifestations, such as nephritis, malar rash, and hemolytic anemia when it is diagnosed.[5],[6] A study on Southeast Asia children showed that the onset of this disease in peripubertal (11–12 years old) was estimated to be 0.3–0.9/100,000 children per year with the predominance in female. However, the incidence was 14.2/100,000 children in Singapore and only 5.3/100,000 in Taiwan. The difference was due to the ethnic composition, ages, and practices in each country.[7] Another study in Vietnam showed that 82% of subjects were diagnosed with lupus nephritis (LN) with high SLEDAI and European College of Laboratory Animal Medicine scores (mean ± standard deviation: 23.8 + 11.6 and 6 + 2.3).[8] On the other hand, a study on West Java, Indonesia, showed that among 97 adult patients, this disease manifests with normocytic normochromic anemia in 59% of patients and microcytic hypochromic anemia in 34% of patients.[9] On jSLE, the most common initial symptoms were prolonged fever, rash, and arthralgia with organ manifestation mostly in the kidney, skin, and joints, in addition to anemia development.[10]

The major medical treatment of jSLE is to control the disease activity to get better outcomes and survival rates. The SLE disease activity is associated with organ damage, outcomes worsening, comorbidities, and mortalities of the patients.[11] SLE fluctuates between active or flares and remission, and the features could vary between individuals.

Various methods were developed to notice the active disease, identify the flares, and predict the flares. The SLEDAI is used to measure the disease activity within 10 days. As a global index, it includes 24 clinical and laboratory variables that are weighted by the type of manifestation but not by severity.[12] Unfortunately, in our hospital, the immunology test (antibody-anti-dsDNA) was not covered by national insurance, so sometimes, it cannot be done. The Mexican- SLEs disease activity index (Mex-SLEDAI) was developed by Mexican researchers to reduce the cost of laboratory tests included in SLEDAI. The Mex-SLEDAI can measure the disease activity as it includes 10 clinical and laboratory variables without any immunology test.[13],[14] The index has been validated and demonstrated to be reliable and sensitive to change.[14]

This study was undertaken to determine the organ manifestation in patients with jSLE at the time of referral and their relationship with disease activity in the hospital.


  Materials and Methods Top


A cross-sectional retrospective study was done in the Allergy Immunology units at a tertiary referral hospital in East Java (Dr. Soetomo Academic Hospital, Surabaya Indonesia).

Patient

The study evaluated 62 patients under 18 years old who fulfilled 4 of 11 1997 American College of Rheumatology (ACR) diagnostic criteria using Mex-SLEDAI. The patients with incomplete clinical documentation of disease onset were excluded. The Health Research Ethics Committee of Dr. Soetomo Surabaya approved the study (Ethical Clearance Number 0077/LOE/301.4.2/VII/2020).

Instrument

The Mex-SLEDAI consists of 10 weighted criteria without an immunology test [Table 1]: Neurologic disorder (8), renal disorder (6), vasculitis (4), myositis (3), arthritis (2), hemolysis and thrombocytopenia (3), mucocutaneous disorder (2), serositis (2), lymphopenia and leucopenia (1) fever, and fatigue (1). The sum of all weighted attribute scores comprises the final Mex-SLEDAI score with the score range between 0 and 32, and ≥5 scores are considered an active disease.[13],[14]
Table 1: The criteria of Mexican-systemic lupus erythematosus activity index

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Patients' clinical variables were obtained using medical history records and physical examinations. Each patient's disease activity was determined using Mex-SLEDAI. Other data, such as hematological, biochemical parameters, chest radiograph and electrocardiogram, antinuclear antibodies (ANA) by immunofluorescence with the (4′,6-Diamidine-2′-phenylindole dihydrochloride) DAPI kit method, anti-dsDNA by enzyme-linked immunosorbent assay eBioscience kit (USA), and complement levels were recorded. We assessed the organ manifestation on patient arrival.

Statistical analysis

All data were analyzed using SPSS ver. 21 (IBM, USA), including the Kolmogorov–Smirnov test of normality and the Levene's Test of Homogeneity, and considered statistically significant if the P < 0.05. Subjects' characteristics, laboratory results, and organ manifestation were analyzed using paired sample t-test, Fischer's Exact Test, and Mann–Whitney U-test (if the data were not normally distributed and not homogeneous), and considered statistically significant if the P < 0.05. Meanwhile, the correlation of organ manifestation and disease activity was analyzed using Spearman's rho correlation. The odds ratio was analyzed using Mantel-Haenszel Common Odds Ratio Estimation.


  Results Top


This study included 62 patients, which were 14 males and 48 females. According to Mex-SLEDAI scores, 39 subjects were defined as active jSLE, and 23 subjects were inactive jSLE with a mean age of 132.21 months old or 11.02 years old. [Table 2] summarizes the subjects' characteristics.
Table 2: Subjects' characteristics

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Subjects with active jSLE ranged from 115.51-114.44 months or 9.63-12.03 years in age, with a mean age of 129.97 ± 44.63 months or 10.75 years. Inactive jSLE subjects ranged from 115.98 months to 155.69 months or 9.63 years to 12.97 years in age, with a mean age of 141.478 ± 38.88 months or 11.79 years old. The bodyweight in active jSLE subjects was 27.28–35.90 kg, while inactive jSLE was 29.51–42.45 kg, and there was no significant difference between them. The body height in active jSLE subjects was 129.54–141.12 cm and 130.16–151.51 cm in inactive jSLE. There was no significant difference in body height between the groups. The BMI of active jSLE ranged from 15.26–17.90 kg/m2 and 15.53–19.35 kg/m2 in inactive jSLE with no significant difference between them. The nutritional status of the jSLE subjects revealed that malnutrition affected 45.16% of all subjects, while 30.65% of respondents were normal or good, and the rest (24.19%) were overweight and obese [Table 2].

[Table 3] presents the laboratory results. Although there was no significant difference between the two groups in complement 3, the level was slightly low in active jSLE. The ANA test result was slightly increased in active jSLE, although there was no significant difference between the groups. White blood cell counts and platelet counts were lower in active jSLE, but there was no significant difference with the inactive one. However, there was a significant difference in anti-dsDNA levels and hemoglobin, in which active jSLE had a higher anti-dsDNA level than inactive jSLE with lower hemoglobin than inactive jSLE.
Table 3: Laboratory test of the subjects

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[Table 4] summarizes the organ manifestation of SLE. Both active and inactive jSLE had skin, hematological, and joint manifestations. However, the proportion of renal manifestation was more prominent in active jSLE. There was a significant difference in both groups, indicating that renal manifestation is one of the clinical signs of disease activity in jSLE than the other organ manifestation. The malar rash incident as the clinical features of skin manifestation (69.23 vs. 41.67%, P = 0.032) and bicytopenia (41.03 vs. 12.5%, P = 0.023) as the hematological manifestation was significantly higher in active jSLE than inactive.
Table 4: Systemic lupus erythematosus organ manifestation in children

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[Table 5] presents the correlation between organ manifestation and disease activity. The spearman's rho correlation revealed that renal manifestation positively correlated with the disease activity than other manifestations.
Table 5: Spearman's rho correlation between organ manifestation with disease activity based on Mexican systemic lupus erythematosus disease activity index scores

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[Table 6] summarizes the odds ratio of organ manifestation and disease activity. In all organ manifestations investigated in this study, renal manifestation had the highest risk in active jSLE, as much as 19.714-fold higher than other organ manifestations.
Table 6: The odds ratio of organ manifestation with disease activity based on Mexican systemic lupus erythematosus disease activity index score

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  Discussion Top


The juvenile-onset of SLE was mostly diagnosed at the age of 13 years old[5] and the peak disease onset is between 12 and 14 years old according to a cohort study.[2] The female/male ratio was mostly 4:3 before the age of 10 years old[5] and increase to 4:1 during the second decade of life.[15] The subjects in this study had a mean age of 11.02 years old and a male/female ratio of 1:3.9, with 9 times greater incidents in females.[16] The predominance of female subjects in SLE is still unknown until now. It is postulated that the elevation of interferon-alpha plays a pathogenic role, and this cytokine is mostly expressed by the placenta.[3] Other stated that female tends to have hypomethylation in DNA that increases the activity of lymphocytes.[17] However, female hormones, like estrogen and prolactin, promote autoimmunity and increase the B-cell activation factor production.[3]

The nutritional status and food intake in SLE may interfere with the disease course. Most SLE had inadequate nutritional status yet almost three-quarters of SLE patients were overweight and obese due to excessive intake of lipids and protein alongside micronutrients deficiencies[18] that lead to overweight and obesity. In addition, the disease activity is correlated with the increase of BMI.[19] It also correlates with the SLE damage index and the elevation of complement serum.[20] The excess weight is associated with the increase of clinical activity and low intake of micronutrients.[18] However, our study revealed that malnutrition is still high in jSLE as it may be due to the effect of chronic inflammatory. It is well known that cytokines potentially inhibit food intake that leads to anorexia, reduced food intake, and reduced body weight.[21] IL-1β, TNF-α, and IL-6 cytokines induce anorexia in the peripheral and central nervous systems and suppress food intake by reducing the meal size and duration.[22] This study revealed no correlation between the nutritional status and the disease activity (‒0.011, P = 0.931), but malnutrition affected the risk of disease activity by 1.740-times (95% CI [0.582–5.202]).

Skin manifestation is common in SLE patients, which occurs in 60%–90% of cases[23] with the feature of erythematosus lesions or discoid[24] and photosensitive. This is in line with this study as we found it in more than 90% of the observed cases. Hematological manifestation in the form of anemia is common in SLE that occurs in about 60%–80% of cases,[25] while leucopenia happens in 42%–75% of SLE subjects. This also correlates with anti-dsDNA levels, mucocutaneous manifestation,[15] and thrombocytopenia, which also occurred on 10-40% of SLE patients, ranging from mild to severe.[26] Thrombocytopenia (platelets <100,000) is one of the prognostic indicators of severe disease and is related to mortality.[27] A study by Munasir et al. obtained thrombocytopenia cases in 5 out of 33 SLE children, and 3 of them died from bleeding.[10] A study in Indonesia showed that hematological manifestation is caused by the presence of the excess and a diverse number of antigens in blood and blood vessels,[28] including cytokines, antibodies, immune complexes, and medication-related toxins.[29] Neurological manifestation occurred in 37% of the patients in the form of psychiatric dysfunction, seizures, and head pain.[29] Musculoskeletal manifestations, such as arthralgia or arthritis, range from 69% to 95% of the cases,[30] and a similar observation also occurred in this study.

jSLE with renal manifestation (odds ratio [OR] = 1.55) and neurological manifestation (OR = 1.64) is more frequent than the adult-onset of SLE.[31] A study of jSLE in Jakarta, Indonesia, found renal manifestation in more than half of the patients.[10] Renal manifestation had a significant correlation and a higher risk of disease activity in jSLE in this study. Severe organ manifestation, including renal and neurological, has been identified as the risk factors for disease activity.[32] Renal manifestation carries a complicated burden to the patients that leads to mortality[1] and it occurs in around 50%–75% of children with SLE.[15] The renal complication is the severe clinical manifestation of jSLE that increases morbidity and mortality by 19-fold while reduces 10-years survival by 88%[4] and quality of life when compared to the subjects without renal manifestation.[33]

Hemoglobin level in active jSLE was significantly lower than inactive jSLE, indicates that the active jSLE subjects suffer from anemia more frequently than inactive jSLE. Anemia occurs in 74.36% of subjects but is not significant between the two groups. One descriptive study conducted in Jakarta obtained that most jSLE children suffer from anemia without any explanation of the cause of anemia.[10]

ANA and double-stranded DNA (anti-dsDNA) are the most common autoantibodies in SLE patients. Anti-dsDNA should be monitored, especially in patients with renal manifestation.[34] The positive result of anti-dsDNA is frequent in jSLE.[15] The elevated level of anti-dsDNA and anti-histone also increased in the organ manifestation cases.[34] A study states that LN is more frequent in subjects with positive anti-dsDNA.[35] The serum level of anti-dsDNA correlates with lupus activity, especially nephritis,[36] and had a direct nephritogenic effect on renal cells and glomerulus complements.[37]

The increase of anti-dsDNA happens several months before the disease flare,[38] accompanied by the decrease of C3 complement.[23],[34] Complement is a component of innate immune response that acts as opsonizing immune complexes for degradation by effector immune cells.[16] It indicates the complement consumption, activation of complement by immune complexes, or deficiency[34] and is found at a low level as the marker of SLE.[23] However, another study stated that anti-dsDNA is not sensitive or specific for detecting the disease activity in the renal.[37] Spearman rho correlation between anti-dsDNA positive results did not correlate with the disease activity (r = 0.012, P = 0.929) and renal manifestation (r = ‒0.063, P = 0.634) in this study. A study stated that 92% of patients with renal manifestation had lower C3 levels and elevated anti-dsDNA levels.[39] Anti-dsDNA, C3 complement, and leukocytopenia are used as inflammatory activity parameters.[32]

The pathology of renal manifestation is due to the alteration of T-cell – mediated immunologic function to form autoantibody targeting tissue-specific antigens, general cellular or extracellular matrix component, and nuclear antigens that leads to the inhabitation of cellular apoptosis through a number of cellular mechanisms. The autoantibodies are able to form immune complexes that are deposited in the kidneys.[16],[40] This condition causes the persistence of autoreactive T cells and triggers the release of abnormal nucleosomes that causes the excess of intraglomerular nucleosomes and eventually, the glomerular immune deposits.[16]


  Conclusions Top


The skin and hematological manifestations are the most typical organ manifestations. The renal manifestation was strongly correlated with disease activity and had the highest risk in active jSLE by 19.714-fold. Advanced prospective research with a repetitive examination is needed for better results.

Acknowledgments

The authors would like to thank Dr. Soetomo Academic Hospital, Surabaya, Indonesia, for supporting this research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

 
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