Childhood-onset systemic lupus erythematosus

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. 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; cutaneous small-vessel vasculitis skin lesions, 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); 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. 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. 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. 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., The American College of Rheumatology has suggested at least one serologic and one non-serological criterium (see below section on "Diagnosis of cSLE") be included in the criteria used to diagnose drug-induced SLE. and aSLE patients treated with vitamin D have significant reductions in the activity of their disease. While other studies have not found these results, it is clear that the serum levels of vitamin D are often low in, and perhaps as a result of having, aSLE. This is particularly the case in cSLE. Vitamin D is obtained by consuming it or its precursors in food and by forming its precursors in the cells of the skin exposed to sunlight (see Vitamin D formation in skin cells). By binding to its receptor, vitamin D increases calcium absorption from the intestine, increases calcium reabsorption from the kidneys, and regulates the immunological functions of macrophages, T cells, and dendritic cells. In consequence, the low levels of vitamin D in cSLE may cause excessive losses of body calcium, hypocalcemia, low bone density, osteoporosis, increased risk of developing bone fractures, The factors that tend to lower vitamin D in individuals with SLE include: a) avoidance of sunlight and ultraviolet light exposure because of SLE-related photosensitivity; b) reduced consumption of vitamin D due to the loss appetite caused by SLE itself and/or the medications used to treat SLE (e.g., glucocorticoids); c) glucocorticoid-induced reductions in vitamin D levels; d) inhibition of the actions of vitamin D receptors by hydroxychloroquine, a drug which is commonly used to treat SLE; and e) low levels of vitamin D production by lupus nephritis-afflicted kidneys (along with the liver, the kidney forms vitamin D from its precursors that were in the diet or formed by sunlight, see the below section "Treatment for vitamin D deficiency in cSLE"). ==Diagnosis of cSLE==

Systemic Lupus International Collaborating Clinics criteria The diagnosis of SLE can be challenging because not one its symptoms or biomarkers by themselves are sufficient to indicate that the disease is SLE. Currently, the diagnosis of SLE depends on finding a combination of criteria that strongly support it. For further details on these criteria see Fonseca, AR et al. developed a different set of criteria for diagnosing SLE in patients aged 2–21 years old. They determined that individuals in this age group had SLE if they had: a) a serum titer of 1:80 or higher for any one of the antinuclear antibodies as measured using cultured HEp-2 cells or other valid measurements of these antibodies and b) one or more of 7 specified constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, renal, or musculoskeletal clinical symptoms plus elevated serum levels of antiphospholipid antibodies, the iC3b split product of complement component 3 and/or 4b split product of complement component 4, and SLE-specific antibodies. Each of these items received a severity score ranging from 2 to 10 with individuals being diagnosed as having cSLE if they receive a summary score of 10 or higher. The sensitivity and specificity scores of these criteria in diagnosing SLE in this age group were 84.8 and 82.8, respectively. Genetic criteria The diagnosis of cSLE in individuals with cSLE-like findings is indicated in individuals with any one of the monogenic gene mutations known to cause cSLE (see the above section on Genetics). The abnormal presence of these mRNAs in tissues is sometimes termed the "interferon signature" or "high interferon signature". ==Treatment==

Individuals with cSLE should be: a) advised to protect themselves against inflammation-inducing ultraviolet light by avoiding, and using sunscreen to block, sunlight; b) counseled on their nutritional needs (e.g., their diets should be low in salt and, if routine checks indicate their vitamin D blood levels are low, contain supplemental vitamin D); and c) offered mental health services if showing signs of depression, anxiety, and/or ineffective family coping. Furthermore, cSLE patients are infection-prone due to their taking immunosuppressive drugs and/or having functional asplenia (i.e., a poorly functioning spleen).Since infections are a common cause of disease flares and mortality in cSLE, cSLE patients should be encouraged to be immunized against Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Clostridium tetani, and Neisseria meningitidis bacteria and against Influenza B, Hepatitis A, Hepatitis B, Papillomaviridae, (which cause warts and various cancers including cervical cancer), and SARS-CoV-2 viruses. Attenuated vaccines, i.e., vaccines containing live but weakened viruses such as the varicella, measles, mumps, rubella, MMR (i.e., combined measles, mumps, and rubella), and yellow fever vaccines are contraindicated for cSLE patients who are immunosuppressed by their disease and/or treatment with immunosuppressing drugs.). The following treatments focus on drugs which suppress the inflammatory component of the cSLE disorders. However, many of these disorders require treatments that in addition to suppressing inflammation treat the serious consequences of the inflammatory reactions such as direct measures to reduce cardiac tamponade and hemodialysis followed by kidney transplantation to treat end-stage kidney failure. The measures used to treat the serious consequences of autoimmune inflammation-induced tissue and organ damage are discussed elsewhere. Hydroxychloroquine is recommended as first-line therapy to treat all cSLE patients unless they have contraindications to taking it. Hydroxychloroquine is an antimalarial drug that also reduces the fatigue, mucosal, and cutaneous symptoms, alopecia, disease flares, and blood lipid levels in cSLE. Since it can damage the retina, annual ophthalmology examinations of hydroxychloroquine-takers are needed to assess retinal changes which if present indicate that the drug should be discontinued.) are used to suppress the intensity of the inflammatory component of cSLE. Topical glucocorticoid ointments are used to treat mild to moderate skin rashes For example, prednisone is used at low doses (equal to or less than 7.5 mg per day), medium doses (greater than 7.5 mg but less than 30 mg per day), or high doses (greater than 30 mg but less than 100 mg per day) to treat mild, moderate, or severe inflammations, respectively, such as those causing neurological, hematologic, and kidney disorders. Pulse dosages of prednisone (i.e., 250 mg per day for one to a few days) may also be used for moderate to severe inflammations. are useful for treating fevers, arthritis, and small pleural and pericardial effusions in cSLE patients. Mycophenolate mofetil is used at an oral daily dosage of 1200 to 1800 mg per square meter of body size (maximum daily dosage of 3000 mg per square meter of body size) as induction and maintenance therapy to treat the proliferative and membranous glomerulonephritis forms of lupus nephritis (see Classification of lupus nephritis and the following section titled "Treatment of lupus nephritis"), to treat psychiatric disease, and to reduce the amount of glucocorticoids needed to treat moderate and severe inflammatory diseases in cSLE. Children taking this drug may develop bone marrow suppression and an increased susceptibility to infections. Belimumab is a monoclonal antibody that inhibits B-cell activating factor and thereby inflammation. It was approved in 2019 by the US Food and Drug Administration to treat the musculoskeletal, cutaneous, and cardiac manifestations of children with cSLE who are over 5 years old. It is given intravenously to cSLE patients with active disease but should not be given to cSLE patients who have active neuropsychiatric cSLE, acute, severe systemic lupus erythematosus disease, or are taking prednisone at doses greater that 1.5 mg per kg per day. Patients taking belimumab have an increased susceptibility to infections. Studies have shown that these drugs help suppress lupus nephritis in adults when combined with other drugs. For example, a regimen consisting of tacrolimus (4 mg per day), mycophenolate mofetil, and a glucocorticoid had a significantly higher response rate in treating adult lupus nephritis than a standard treatment regimen consisting of cyclophosphamide plus glucocorticoids. The incidence of adverse reactions to the two regimens was similar. It has therefore been suggested that regimens including a calcineurin inhibitor may be useful and should be studied for treating lupus nephritis in cSLE patients. Bortezomib given intravenously or subcutaneously reversed or greatly reduced cSLE-related encephalopathic neuropsychiatric disorders in a recent study of 5 patients. These disorders were auditory hallucinations and insomnia in all 5 patients, suicidal ideation in 4 of the patients, visual hallucinations in 3 of the patients, homicidal ideation in 2 of the patients, hyper-religiosity along with fabricated languages in 2 of the patients, high combativity in 2 of the patients, mania in 1 of the patients, a conversion disorder with echolalia, tinnitus, and tics in 1 of the patients, and anxiety along with a mood disorder in 1 of the patients. All 5 patients developed hypogammaglobulinemia (immunoglobulin G less than 500 mg per deciliter of blood) that required replacing the immunoglobulin for the 1–10 years that the patients were treated with bortezomib. Patient 3 had a brief episode of hypotension after the administration of intravenous bortezomib. Further studies are needed to confirm and expand these promising results. Treatment of lupus nephritis Lupus nephritis not only leads to kidney failure, it is also one of the most common as well as most serious and potentially lethal disorders in cSLE and aSLE. These classes and their respective treatments are: b) an ACE1 inhibitor, or c) an ARB. • Class VI, also termed advanced sclerosing lupus nephritis or Glomerulosclerosis, is poorly responsive to all therapies but progresses to kidney failure very slowly. Class III and IV (also termed the proliferative lupus nephritises) have the worst prognoses and account for up to 75% of all lupus nephritis cases in cSLE. The International Society of Nephrology and Renal Pathology Society revised this classification in 2018 by dividing each class into levels of severity with increasing scores and defining their severity and treatments based on total scores. We use the 2002 classification because the studies reported here were based on it. ==Prognosis==

The prognosis of cSLE and aSLE have improved over the past 50 years. The 10-year survival rate of cSLE patients treated in rheumatology multidisciplinary clinics rose from 78% in the 1970s to 85% in the 2000s. Similarly, the 10 year survival rates in Japan were 92.3% for 1980-1994 and 98.3% for 1995–2006. Another study found that cSLE patients had a 19% higher mortality than their age-matched general population. and a study in 2020 suggested that the survival rate of lupus nephritis in children and adults has not improved over the recent years. Since delayed diagnosis and treatment of lupus nephritis results in higher incidences of kidney failure, it should be quickly diagnosis and properly treated. As more patients have survived well past the early course of their disease, premature atherosclerosis has increasingly contributed to the mortality in cSLE and aSLE. == References ==