Childhood-onset systemic lupus erythematosus (i.e., cSLE), also termed juvenile-onset systemic lupus erythematosus, juvenile systemic lupus erythematosus, and pediatric systemic lupus erythematosus, is a form of the chronic inflammatory and autoimmune disease, systemic lupus erythematosus (SLE), that develops in individuals up to 18 years old. Early-onset systemic lupus erythematosus is often used to designate a subset of cSLE patients who are up to 5 years old. Children with early-onset SLE tend to have a more severe form of cSLE than children who develop cSLE after 5 years of age.
cSLE does not include neonatal lupus erythematosus (nSLE). nSLE is a SLE-like disease that is present in infants at birth. It is caused by certain antinuclear antibodies, e.g., the immunoglobulin G types of the anti-SSA/Ro autoantibodies (e.g., anti-Ro/SS-A and anti-La/SS-B) and anti-nRNP (also termed anti-U1RNP). These antibodies form in the mother and pass from her circulation through the placenta to the fetus where they cause an often severe form of SLE that is evident in the fetus and newborn child. Most of the disorders in the infants disappear within months as these antibodies are naturally cleared from the infant. However, one disorder occurring in nSLE, congenital heart block, usually does not reverse and is potentially lethal. Fetuses and neonates with this heart block are implanted with an artificial cardiac pacemaker. However, recent studies have shown that hydroxychloroquine given to the mother in her 6th and 10th gestational weeks or intravenous immunoglobulin therapy given to the mother in her 14 and 18 gestational weeks reduces the incidence of developing this heart block (Intravenous immunoglobulins given to the mother suppress her production of antibodies including those that cause nSLE.).
cSLE, similar to adult-onset SLE (i.e. aSLE), is caused by an individual's production of antibodies that bind to antigens located in the individual's own cells' nuclei and cytoplasm. These antibody-antigen complexes trigger uncontrolled inflammation and injury in various tissues and organs (see below section on "Inflammation"). 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. While there are similarities between the childhood and adult forms of SLE (i.e., aSLE), cSLE has several characteristics that make it a clinical entity distinct from aSLE. For example, cSLE has a more aggressive disease onset and course, more frequent disease exacerbations, more severe organ damages, and a higher mortality rate than aSLE.
Presentation cSLE occurs more frequently in Black, Asian, Hispanic, and Native American than Caucasian populations and is more frequently diagnosed in individuals from urban than rural areas. The median age at the onset of cSLE was 12.6 years in a review of 196 cases conducted in the United Kingdom. Patients with cSLE may present with tissue-injuring and blood vessel-injuring (termed lupus vasculitis) inflammation in the: a) kidneys, causing various types of kidney damages e.g., lupus nephritis and kidney failure, and thereby hypertension, i.e., high blood pressure; b) central nervous system, causing headaches, seizures, cerebrovascular disease, strokes, and neuropsychiatric systemic lupus erythematosus encephalopathies such as mood disorders, cognitive disorders, and psychoses; c) lung, causing pleuritis, pneumonitis (termed acute lupus pneumonitis), pulmonary hypertension, pulmonary hemorrhages, and a form of restrictive lung disease in which the lung has shrunk in size (this condition is termed the "shrinking lung syndrome", see rheumatoid lung disease); d) gastrointestinal tract, causing peritonitis and intestinal pseudo-obstructions; e) heart, causing pericarditis, myocarditis, endocarditis, and cardiac tamponade (i.e., pericardial fluid that compresses the heart); f) pancreas, causing pancreatitis, hyperlipidemia and, as a long-term consequence of hyperlipidemia, atherosclerosis and myocardial infarctions (i.e., heart attacks); g) joints, causing non-deforming arthritis and in rare cases the deforming arthritis, Jaccoud arthropathy; h) skeletal muscles, causing muscle pain and tenderness that may be accompanied by the same types of rashes, arthritides, and arthralgias that occur in the inflammatory muscle disease, dermatomyositis; and i) skin and mucous membranes, causing active and chronic lesions such as a malar rash, discoid rash (see discoid type rash), photodermatitis, oral/nasopharyngeal ulcers, cutaneous small-vessel vasculitis skin lesions, and in rare cases chilblain lupus erythematosus. cSLE may also present as autoimmune-induced decreases in the blood levels of platelets termed immune thrombocytopenic purpura), red blood cells termed autoimmune hemolytic anemia, leukocytes termed leukopenia, neutrophils termed neutropenia (neutrophils are a type of leukocyte), and lymphocytes termed lymphopenia. Patients with cSLE may also develop thrombotic microangiopathy, a severe disease caused by the aggregation of blood platelets in, and thereby partial occlusion of, the blood flow to and dysfunction of multiple organs including in particular the brain and kidneys. Individuals with cSLE-related thrombotic microangiopathy may also exhibit thrombocytopenia and/or hemolytic anemia. Fatigue is also a frequent complaint of children presenting with cSLE. Finally, cSLE patients on rare occasions develop functional asplenia (i.e., a poorly functioning spleen) that increases their susceptibility to infections.
Studies have shown that the presentations and extents of disease differ in patients with cSLE and aSLE. For example: a) cSLE afflicts 4–5 females to 1 male while aSLE afflicts 9 females to 1 male; b) cSLE involves the kidneys in 60–80% and aSLE in 35–50% of cases; c) cSLE involves the central nervous system in 20–50% and aSLE in 10–25% of cases; d) cSLE involves the lung in 15–40% and aSLE in 20–90% of cases; e) SLE involves the joints in 60–70% and aSLE in and 80–95% of cases; f) cSLE has a more aggressive disease and therefore requires more intensive therapy than aSLE; g) genetic disorders more often underlie the development of cSLE than aSLE (see "Genetics" in next section); and h) drug-induced SLE has been reported far less frequently in cSLE than aSLE (see "Drugs" next section). There are also some differences is the presentation of cSLE in different populations. For example, a study conducted in Japan reported that patients diagnosed with cSLE presented with a malar rash (73.1% of cases), discoid rash (17.7%), photosensitivity (23.1%), arthritis (33.3%), serositis (9.7%), hemolytic anemia (12.4%), and leukopenia (52.2%). In contrast, patients in Turkey diagnosed with cSLE presented with a malar rash (60.8%), discoid rash (11.8%), photosensitivity (44.1%), arthritis (46.1%), serositis (16.7%), hemolytic anemia (17.6%), and leucopenia (33.3%).
Causes Inflammation SLE is caused by a not yet well understood generation of inflammation-inducing antibodies (termed autoantibodies) that attack an individual's own antigens. These autoantibodies, none of which are present in all cases of SLE, include the: a) antinuclear (i.e., ANA) and anti-dsDNA antibodies; b) anti-Sm, anti-RNP, anti-SSA, and anti–SS-B antibodies (anti-SSA and anti-SS-B antibodies are associated with less severe forms of cSLE);) c) antiphospholipid autoantibodies including the lupus anticoagulant, anti-cardiolipin, and anti-apolipoprotein autoantibodies; and d) anti-histone antibodies (anti-histone antibodies are associated with drug-induced SLE). When bound to their target antigens, these autoantibodies form immune complexes which attract and activate T cells, B cells, and other inflammation-inducing leukocytes. In addition, the antibody-antigen complexes are engulfed by plasmacytoid dendritic cells that then produce type I interferons which act to further promote the inflammation responses. More than 95% of individuals with cSLE display a type I IFN signature, i.e., increased whole blood, blood cells, or tissue levels of the messenger RNAs (i.e., mRNAs) for the type 1 interferons.
Gene mutations 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 aSLE. The genes that have certain mutations which cause aSLE are termed as acting in a "monogenic" or "single-gene" manner. They include 5 that are classified as inborn errors of immunity genes, i.e., the DNASE1L3, TREX1, IFIH1, Tartrate-resistant acid phosphatase, and PRKCD genes and 29 other genes, i.e., NEIL3, TMEM173, ADAR1, NRAS, SAMHD1, SOS1, FASLG, FAS, 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, TLR7, UNC93B1 (Mutations in the UNC93B1 gene cause either SLE or the chilblain lupus erythematosus variant of SLE.), and two complement component 4 genes, C4A and C4B. The C4A and C4B genes code respectively for complement component A and complement component B proteins. The two proteins made by these genes 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 genes but develop SLE if they have a mutation in one of them that significantly reduces the number of its copies. While it is suggested that any of these gene mutations may cause cSLE, the monogenetic mutations to date documented to cause cSLE include only 10 genes, i.e., IFIH1, DNASE1L3, TLR7, complement component 1qA, complement component 1qB, complement component 1r, complement component 1s, complement component 2, C4a, and C4B. However, a 2018 review of 44 patients with aSLE found that 9 had dramatically decreased plasma levels of N1-acetylcadaverine, spermidine, N1-acetylspermidine, and spermine. This could be due to inactivating mutations in SAT1, the gene encoding spermidine/spermine N1-acetyltransferase, an enzyme that makes these metabolites. A recent study reported that loss of function mutations in the SAT1 gene were present in two unrelated African American mothers and two boys in each of their families. Since the SAT1 gene is on the X-chromosome and only one of their two X- chromosomes carried this mutated gene, the mothers of these children had one normal SAT1 gene and therefore did not have decreases in the cited 4 metabolites or cSLE. In contrast, the two boys (males carry only one X-chromosome) in each family had the mutated SAT1 gene, had dramatically depressed plasma levels of these metabolites, and developed cSLE (see X-linked recessive inheritance). Although further studies are needed, these results suggest that loss of function mutations in the SAT1 gene cause cSLE and may also do so in aSLE.
Mutations in a wide range of other genes do not by themselves cause SLE but act in concert with other genes, environmental factors, or unknown factors in some but not other populations to cause SLE. The development of a genetically regulated trait or disorder that is dependent on the inheritance of two or more mutated genes is termed oligogenic inheritance or polygenic inheritance. The article published by Sestan, et al., lists more than 110 genes that must act in cooperation with other factors to promote the development of aSLE and/or cSLE.
Drugs