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Childhood-onset systemic lupus erythematosus (i.e., cSLE), also termed juvenile-onset systemic lupus erythematosus, juvenile systemic lupus erythematosus, or pediatric systemic lupus erythematosus, is a variant of the chronic inflammatory autoimmune disease, systemic lupus erythematosus (i.e., SLE), that occurs in individuals before they reach 18 years old.[1] Early-onset systemic lupus erythematosus is often used to designate a subset of cSLE patients who are younger than 5 years old and trend to have a more severe form of cSLE than older children. However, cSLE does not include neonatal lupus erythematosus (nSLE), an SLE-like disease that is present at birth. Unlike cSLE, nSLE is caused by the transport of certain antinuclear antibodies, e.g., tth anti-SSA/Ro autoantibodies anti-Ro/SS-A and anti-La/SS-B, and, less often, the anti-nRNP antibody, anti-U1RNP. The immunoglobulin G forms of on or more of these or in rarer cases other inflammation-causing antibodies pass from the mother's circulation through the placenta into her fetus where they cause an often sever form of cSLE in the embryo. The mothers of nSLE-afflicted embryos and neonates (i.e., babies during first 28 days after birth) have in about half of the cases SLE or another autoimmune disease.[2]

cSLE, similar to adult SLE, is caused by the afflicted individuals' production of antibodies that target nuclear and cytoplasmic self-antigens to cause inflammatory reactions. These inflammatory reactions may occur in nearly any tissue or organ or throughout the body. About 15 to 20% of individuals with these SLE inflammatory reactions develop them before the age of 18 years and therefore are diagnosed as having cSLE.[3] Worldwide, the prevalence of cSLE is 1.9–25.7 per 100,000 children and its incidence is 0.3–0.9 per 100,000 per year.[4] While there are similarities between the childhood and adult forms of SLE, cSLE has several unique characteristics that make it a clinical entity distinct from adult SLE. For example, cSLE often has a more aggressive disease onset and course, more frequent disease exacerbations, more severe organ damage, and a higher risk of mortality than adult SLE.[1][3][4]

Presentation

[edit]

Individuals with cSLE commonly present with one or more of the following autoinflammation-induced disorders that involve the: a) kidneys causing lupus nephritis which is a severe form of glomerulonephritis that may lead to kidney failure;[5] b) central nervous system causing headaches, seizures, and encephalopathies such as mood disorders, cognitive disorders, and psychoses;[6][7] c) lung causing pleuritis, pneumonitis (termed acute lupus pneumonitis), a form of restrictive lung disease termed shrinking lung syndrome, pulmonary hypertension, and pulmonary hemorrhages; d) gastrointestinal tract causing lupus vasculitis (i.e., damage to blood vessels that serve the gastrointestinal tract), pancreatitis, peritonitis, and intestinal pseudo-obstructions;[8][9] e) heart causing pericarditis, myocarditis, endocarditis, atherosclerosis, and in extremely rare cases myocardial infarctions, i.e., heart attacks;[9] f) joints causing arthritis; g) skin and mucous membranes causing active and chronic lesions in these tissues such as the malar rash, discoid rash (see discoid type rash), photodermatitis, oral or nasopharyngeal ulcers,[10] and in rare cases chilblain lupus erythematosus.[11]

Based on multiple studies, cSLE's presentation and extent of disease differs from adult SLE (aSLE) in that cSLE afflicts 4–5 girls to 1 boy while aSLE afflicts 9 females to 1 male; cSLE involves the kidneys in 60–80% and aSLE in 35–50% of cases; cSLE involves the central nervous system in 20–50% and cSLE in 10–25% of cases; cSLW involves the lung in 15–40% and aSLE in 20–90% of cases; cSLE involves the joints in 60–70% and aSLE in and 80–95% of cases; cSLE presents with, takes a more aggressive course, and therefore requires more intensive therapy than aSLE; and genetic disorders more often underlie the development of cSLE than aSLE (see next section).[3]

Causes

[edit]

Genetics

[edit]

Studies of identical twins (i.e., twins that develop from the same fertilized egg) and genome-wide association studies have identified numerous genes that when having certain types of mutations cause the development of SLE and/or cSLE.[3][12][13] These monogenic (also termed single-gene[1]) mutations have been identified in about 40 genes.[13] The genes include 5 which as of February, 2024 were classified as inborn errors of immunity genes, i.e., DNASE1L3, TREX1, IFIH1, Tartrate-resistant acid phosphatase, and PRKCD[14][15][16] and 29 other genes, i.e., NEIL3, TMEM173, ADAR1, NRAS, SAMHD1, SOS1, FASLG, FAS receptor gene, RAG1, RAG2, DNASE1, SHOC2, KRAS, PTPN11, PTEN, BLK, RNASEH2A, RNASEH2B, RNASEH2C, Complement component 1qA, Complement component 1qB, Complement component 1r, Complement component 1s, Complement component 2, Complement component 3, UNC93B1, TLR7 and the two complement component 4 genes ,C4A and C4B.[3][14][17][11][18] (The C4A and C4B genes code respectively for complement component A and complement component B proteins. These two proteins combine to form the complement component 4 protein which plays various roles in regulating immune function. Individuals normally have multiple copies of the C4A and C4B gene but if they have reduced levels of one and/or both of these genes make low levels of complement component 4 protein and thereby are at risk for developing cSLE or a cSLE-like disorders.[19][20])(Note that mutations in the UNC93B1 gene may cause either SLE or the chilblain lupus erythematosus form of SLE.[11])

Vitamin D deficiency

[edit]

Various studies have reported that vitamin D deficiency often occurs in patients with aSLE; that vitamin D levels are particularly low in patients with more active aSLE;[21][22] and that aSLE patients treated with vitamin D have significant reductions in the activity of their disease.[23] However, other studies have not found these results.[24] It is clear that serum vitamin D levels may be low as a result of being treated for SLE. This is particularly the case with cSLE patients who, if not treated with supplemental vitamin D, commonly have low levels of the two active vitamin A forms, 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.


Childhood-onset systemic lupus erythematosus (i.e., cSLE), also termed juvenile-onset systemic lupus erythematosus, juvenile systemic lupus erythematosus, or pediatric systemic lupus erythematosus, is a variant of the chronic inflammatory autoimmune disease, systemic lupus erythematosus (i.e., SLE), that occurs in individuals before they reach 18 years old.[1] Early-onset systemic lupus erythematosus is often used to designate a subset of cSLE patients who are younger than 5 years old and trend to have a more severe form of cSLE than older children. However, cSLE does not include neonatal lupus erythematosus (nSLE), an SLE-like disease that is present at birth. Unlike cSLE, nSLE is caused by the transport of certain antinuclear antibodies, e.g., tth anti-SSA/Ro autoantibodies anti-Ro/SS-A and anti-La/SS-B, and, less often, the anti-nRNP antibody, anti-U1RNP. The immunoglobulin G forms of on or more of these or in rarer cases other inflammation-causing antibodies pass from the mother's circulation through the placenta into her fetus where they cause an often sever form of cSLE in the embryo. The mothers of nSLE-afflicted embryos and neonates (i.e., babies during first 28 days after birth) have in about half of the cases SLE or another autoimmune disease.[2]

cSLE, similar to adult SLE, is caused by the afflicted individuals' production of antibodies that target nuclear and cytoplasmic self-antigens to cause inflammatory reactions. These inflammatory reactions may occur in nearly any tissue or organ or throughout the body. About 15 to 20% of individuals with these SLE inflammatory reactions develop them before the age of 18 years and therefore are diagnosed as having cSLE.[3] Worldwide, the prevalence of cSLE is 1.9–25.7 per 100,000 children and its incidence is 0.3–0.9 per 100,000 per year.[4] While there are similarities between the childhood and adult forms of SLE, cSLE has several unique characteristics that make it a clinical entity distinct from adult SLE. For example, cSLE often has a more aggressive disease onset and course, more frequent disease exacerbations, more severe organ damage, and a higher risk of mortality than adult SLE.[1][3][4]

Presentation

[edit]

cSLE commonly presents with one or more of the autoinflammation-induced injuries to the: a) kidneys causing lupus nephritis which is a severe form of glomerulonephritis often leading to kidney failure;[5] b) central nervous system causing encephalopathies such as mood disorders, cognitive disorders, and seizures;[7] c) lung causing pleuritis, pneumonitis (termed acute lupus pneumonitis), a form of restrictive lung disease termed shrinking lung syndrome, pulmonary hypertension, and pulmonary hemorrhages; d) the gastrointestinal tract causing Lupus vasculitis, pancreatitis, peritonitis, and intestinal pseudo-obstructions; e) the heart causing pericarditis, myocarditis, endocarditis, atherosclerosis, and in extremely rare cases myocardial infarctions, i.e., heart attacks;[9] f) joints causing arthritis in various joints; g) skin and mucous membranes causing active and chronic lesions in these tissues such as the malar rash, discoid rash (see discoid type rash), photodermatitis, oral or nasopharyngeal ulcers,[10] and in very rare cases [[chilblain lupus.[11] erythematosus]]

Causes

[edit]

Vitamin D deficiency

[edit]

Some studies have found that vitamin D deficiency (i.e., a low serum level of vitamin D) often occurs in patients with SLE and that its level is particularly low in patients with more active SLE.[25][22] Furthermore, 5 studies reported that SLE patients treated with vitamin D had significant reductions in the activity of their disease.[23] However, other studies have found that the levels of vitamin D in SLE are not low, that vitamin D does not reduce their SLE's activity, and/or that the vitamin D levels and responses to vitamin D treatment varied in different patient populations (i.e., varied based on whether the study was conducted on individuals living in Africa or Europe). Because of these conflicting findings, the following middle ground has been proposed for using vitamin D to treat SLE: a) patients with SLE that have 25-hydroxyvitamin D2 plus 25-hydroxyvitamin D3 serum levels less than 30 ng/ml should be treated with vitamin D to keep these levels at or above 30 ng/ml or, in patients having major SLE-related organ involvement, at 36 to 40 ng/ml and b) patients with 25-hydroxyvitamin D2 plus 25-hydroxyvitamin D3 levels at or above 30 ng/ml should not be treated with vitamin D unless they have major SLE-related organ involvement in which case they should be treated with 25-hydroxyvitamin D2 plus 25-hydroxyvitamin D3 to maintain their serum vitamin D levels between 36 and 40 ng/ml.[24]

Genetics

[edit]

Studies of identical twins (i.e., twins that develop from the same fertilized egg) and genome-wide association studies have identified numerous genes that by themselves promote the development of SLE, particularly childhood-onset SLE, i.e., cSLE, in rare cases of SLE/cSLE.[12][13][3] The single-gene (also termed monogenic) causes of cSLE (or a cSLE-like disorder) develop in individuals before they reach 18 years of age. cSLE typically is more severe and potentially lethal than adult-onset SLE because it often involves SLE-induced neurologic disease, renal failure, and/or the macrophage activation syndrome.[1] Mutations in about 40 genes have been reported to cause cSLE and/or a cSLE-like disease.[13] These genes include 6 which as of February, 2024 were classified as inborn errors of immunity genes, i.e., DNASE1L3, TREX1, IFIH1, SH50, Tartrate-resistant acid phosphatase and PRKCD[14][15][16] and 35 other genes, i.e., NEIL3, TMEM173, ADAR1, NRAS, SAMHD1, ANAPC5 (also termed APC5), TNFRSF6, SOS1, FASLG, RAG2, DNASE1, PSMA3, PSMB4, PSMB8, SHOC2, KRAS, PTPN11, PTEN, BLK, Bank1, CYBB, RNASEH2A, RNASEH2B, RNASEH2C, LRBA, CD70, Complement component 1qA, Complement component 1qB, Complement component 1r, Complement component 1s, Complement component 2, Complement component 3, UNC93B1, and the two complement component 4 genes ,C4A and C4B,[14][17][11] (The C4A and C4B genes code respectively for complement component A and complement component B proteins. These two proteins combine to form the complement component 4 protein which plays various roles in regulating immune function. Individuals normally have multiple copies of the C4A and C4B gene but if they have reduced levels of one and/or both of these genes make low levels of complement component 4 protein and thereby are at risk for developing cSLE or a cSLE-like disorders.[19][20])(Note that mutations in the UNC93B1 gene may cause either cSLE or the chilblain lupus erythematosus form of cSLE.[11])

Mutations in a wide range of other genes do not by themselves cause SLE but two or more of them may act together, act in concert with environmental factors, or act in some but not other populations (e.g., cause SLE in Chinese but not Europeans) to cause SLE or an SLE-like syndrome but do so in only a small percentage of cases.[13][26] The development of a genetically-regulated trait or disorder that is dependent on the inheritance of two or more genes is termed oligogenic inheritance or polygenic inheritance.[27][28]

SLE is regarded as a prototype disease due to the significant overlap in its symptoms with other autoimmune diseases.[29]>

References

[edit]
  1. ^ a b c d e f Sura A, Failing C, Co DO, Syverson G (June 2024). "Childhood-Onset Systemic Lupus Erythematosus". Pediatrics in Review. 45 (6): 316–328. doi:10.1542/pir.2023-006011. PMID 38821900.
  2. ^ a b Liszewska A, Woźniacka A (December 2022). "Neonatal lupus erythematosus - prevention is better than cure". Postepy Dermatologii I Alergologii. 39 (6): 1021–1026. doi:10.5114/ada.2022.122601. PMC 9837598. PMID 36686025.
  3. ^ a b c d e f g h Sestan M, Kifer N, Arsov T, Cook M, Ellyard J, Vinuesa CG, Jelusic M (July 2023). "The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus". Current Issues in Molecular Biology. 45 (7): 5981–6002. doi:10.3390/cimb45070378. PMC 10378459. PMID 37504294.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ a b c d Pennesi M, Benvenuto S (October 2023). "Lupus Nephritis in Children: Novel Perspectives". Medicina (Kaunas, Lithuania). 59 (10). doi:10.3390/medicina59101841. PMC 10607957. PMID 37893559.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ a b Sakamoto AP, Silva CA, Islabão AG, Novak GV, Molinari B, Nogueira PK, Pereira RM, Saad-Magalhães C, Clemente G, Piotto DP, Aikawa NE, Pitta AC, Trindade VC, Appenzeller S, Carvalho LM, Rabelo-Junior CN, Fonseca AR, Sztajnbok FR, Santos MC, Bica BE, Sena EG, Moraes AJ, Fraga MM, Robazzi TC, Spelling PF, Scheibel IM, Cavalcanti AS, Matos EN, Guimarães LJ, Santos FP, Mota LM, Bonfá E, Terreri MT (June 2023). "Chronic kidney disease in patients with childhood-onset systemic lupus erythematosus". Pediatric Nephrology (Berlin, Germany). 38 (6): 1843–1854. doi:10.1007/s00467-022-05811-y. PMID 36409367.
  6. ^ Ulloa AC, Liao F, Carlomagno RL, Diaz T, Dominguez D, Levy DM, Ng L, Knight AM, Hiraki LT (February 2022). "Schizophrenia Genetics and Neuropsychiatric Features in Childhood-onset Systemic Lupus Erythematosus". The Journal of Rheumatology. 49 (2): 192–196. doi:10.3899/jrheum.210363.
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  16. ^ a b Yu JE (February 2024). "New primary immunodeficiencies 2023 update". Current Opinion in Pediatrics. 36 (1): 112–123. doi:10.1097/MOP.0000000000001315. PMID 38001560.
  17. ^ a b Wolf C, Lim EL, Mokhtari M, Kind B, Odainic A, Lara-Villacanas E, Koss S, Mages S, Menzel K, Engel K, Dückers G, Bernbeck B, Schneider DT, Siepermann K, Niehues T, Goetzke CC, Durek P, Minden K, Dörner T, Stittrich A, Szelinski F, Guerra GM, Massoud M, Bieringer M, de Oliveira Mann CC, Beltrán E, Kallinich T, Mashreghi MF, Schmidt SV, Latz E, Klughammer J, Majer O, Lee-Kirsch MA (February 2024). "UNC93B1 variants underlie TLR7-dependent autoimmunity". Science Immunology. 9 (92): eadi9769. doi:10.1126/sciimmunol.adi9769. PMID 38207055.
  18. ^ Al-Azab M, Idiiatullina E, Liu Z, Lin M, Hrovat-Schaale K, Xian H, Zhu J, Yang M, Lu B, Zhao Z, Liu Y, Chang J, Li X, Guo C, Liu Y, Wu Q, Chen J, Lan C, Zeng P, Cui J, Gao X, Zhou W, Zhang Y, Zhang Y, Masters SL (June 2024). "Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus". Nature Immunology. 25 (6): 969–980. doi:10.1038/s41590-024-01846-5. PMC 11147776. PMID 38831104.
  19. ^ a b Pereira KM, Perazzio S, Faria AG, Moreira ES, Santos VC, Grecco M, da Silva NP, Andrade LE (August 2019). "Impact of C4, C4A and C4B gene copy number variation in the susceptibility, phenotype and progression of systemic lupus erythematosus". Advances in Rheumatology (London, England). 59 (1): 36. doi:10.1186/s42358-019-0076-6. PMID 31387635.
  20. ^ a b Marin WM, Augusto DG, Wade KJ, Hollenbach JA (January 2024). "High-throughput complement component 4 genomic sequence analysis with C4Investigator". HLA. 103 (1): e15273. doi:10.1111/tan.15273. PMC 11099535. PMID 37899688.
  21. ^ Schneider L, Dos Santos AS, Santos M, da Silva Chakr RM, Monticielo OA (August 2014). "Vitamin D and systemic lupus erythematosus: state of the art". Clinical Rheumatology. 33 (8): 1033–1038. doi:10.1007/s10067-014-2530-5. PMID 24573738. S2CID 28033436.
  22. ^ a b Athanassiou L, Kostoglou-Athanassiou I, Koutsilieris M, Shoenfeld Y (April 2023). "Vitamin D and Autoimmune Rheumatic Diseases". Biomolecules. 13 (4): 709. doi:10.3390/biom13040709. PMC 10135889. PMID 37189455.
  23. ^ a b Irfan SA, Ali AA, Shabbir N, Altaf H, Ahmed A, Thamara Kunnath J, Divya Boorle NV, Miguel AK, Loh CC, Gandrakota N, Ali Baig MM (June 2022). "Effects of Vitamin D on Systemic Lupus Erythematosus Disease Activity and Autoimmunity: A Systematic Review and Meta-Analysis". Cureus. 14 (6): e25896. doi:10.7759/cureus.25896. PMC 9278795. PMID 35844337.
  24. ^ a b Ho LJ, Wu CH, Luo SF, Lai JH (September 2024). "Vitamin D and systemic lupus erythematosus: Causality and association with disease activity and therapeutics". Biochemical Pharmacology. 227: 116417. doi:10.1016/j.bcp.2024.116417. PMID 38996931.
  25. ^ Schneider L, Dos Santos AS, Santos M, da Silva Chakr RM, Monticielo OA (August 2014). "Vitamin D and systemic lupus erythematosus: state of the art". Clinical Rheumatology. 33 (8): 1033–1038. doi:10.1007/s10067-014-2530-5. PMID 24573738. S2CID 28033436.
  26. ^ Yang W, Ng P, Zhao M, Hirankarn N, Lau CS, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Avihingsanon Y, Lee TL, Ho MH, Lee PP, Wong WH, Lau YL (April 2009). "Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese". Genes and Immunity. 10 (3): 219–26. doi:10.1038/gene.2009.1. PMID 19225526.
  27. ^ Kousi M, Katsanis N (June 2015). "Genetic modifiers and oligogenic inheritance". Cold Spring Harbor Perspectives in Medicine. 5 (6): a017145. doi:10.1101/cshperspect.a017145. PMC 4448705. PMID 26033081.
  28. ^ Crouch DJ, Bodmer WF (August 2020). "Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants". Proceedings of the National Academy of Sciences of the United States of America. 117 (32): 18924–18933. Bibcode:2020PNAS..11718924C. doi:10.1073/pnas.2005634117. PMC 7431089. PMID 32753378.
  29. ^ Prokunina L, Alarcon-Riquelme M (April 2004). "The genetic basis of systemic lupus erythematosus--knowledge of today and thoughts for tomorrow". Human Molecular Genetics. 13 Spec No 1 (90001): R143–R148. doi:10.1093/hmg/ddh076. PMID 14764622.
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