Childhood-onset systemic lupus erythematosus

cSLE occurs more frequently in Black, Asian, Hispanic, and Native American than Caucasian populations^[8][9] and is more frequently diagnosed in individuals from urban than rural areas.^[7] The median age at the onset of cSLE was 12.6 years in a review of 196 cases conducted in the United Kingdom.^[10] 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;^[1][11][12] b) central nervous system, causing headaches, seizures, cerebrovascular disease, strokes, and neuropsychiatric systemic lupus erythematosus encephalopathies such as mood disorders, cognitive disorders, and psychoses;^[13][14][15] 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;^[16][17] 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);^[1][17][18] 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;^[1] 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,^[19] cutaneous small-vessel vasculitis skin lesions,^[9] and in rare cases chilblain lupus erythematosus.^[20] 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.^[1][21] 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.^[1][22] Fatigue is also a frequent complaint of children presenting with cSLE.^[23][24] Finally, cSLE patients on rare occasions develop functional asplenia (i.e., a poorly functioning spleen) that increases their susceptibility to infections.^[25]

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);^[6] and h) drug-induced SLE has been reported far less frequently in cSLE than aSLE (see "Drugs" next section).^[26] 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%).^[27] 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%).^[28]

SLE is caused by a not yet well understood generation of inflammation-inducing antibodies (termed autoantibodies) that attack an individual's own antigens.^[29] 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);^[30]) 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.^[31] 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.^[5][32][33]

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.^[6][34][35] The genes that have certain mutations which cause aSLE are termed as acting in a "monogenic" or "single-gene" manner.^[1] They include 5 that are classified as inborn errors of immunity genes,^[36][37][38] 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.^[20]), and two complement component 4 genes, C4A and C4B.^{[6][20][36][39][40]} 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.^[41][42] 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.^[6][43] 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.^[44][45] 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.^[45]

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.^[35][46] 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.^[47][48] The article published by Sestan, et al.,^[6] lists more than 110 genes that must act in cooperation with other factors to promote the development of aSLE and/or cSLE.

Drug-induced SLE is an autoimmune disease in which individuals develop clinical features similar to that in SLE after taking a drug. It is estimated to represent 10% to 12% of all SLE cases.^[26] Although there are no established criteria for diagnosing drug-induced SLE, most reports used the following criteria: afflicted individuals had a sufficient and continuing exposure to the drug, at least one symptom seen in SLE, no history of SLE symptoms before starting the drug, and resolution of their drug-induced symptom(s) within weeks or months after discontinuing the offending drug.^[49] 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.^[26] The VigiBase drug safety data repositor reviewed 12,166 cases of drug-induced aSLE that were recorded between 1968 and 2017. Among the 118 drugs causing these aSLE cases, five main drug classes were most often associated with the development of aSLE: a) various inhibitors of tumor necrosis factor; b) antiarrhythmic agents such as procainamide and quinidine; c) antihypertensive agents such as hydralazine, captopril, and acebutolol; d) antimicrobial agents such as minocycline, isoniazid, carbamazepine, and phenytoin; e) anticonvulsants such as carbamazepine; and f) polyinosinic:polycytidylic acid (an artificial interferon inducer).^[49]

There are fewer reports of drug-induced SLE in children than adults. In a review of 65 cases described in the English language, Kaya Akca, U. et al., 2024^[26] reported that cSLE was caused by ethosuximide (13 cases), minocycline (12 cases), ethosuximide combined with a hydantoin (3 cases), propylthiouracil combined with sulphasalazine (3 cases), carbamazepine (3 cases), cysteamine (2 cases), etanercept (2 cases), isoniazid (2 cases), trimethadione combined with ethosuximide and hydantoin (2 cases), and single cases of adalimumab, cefepime, dapsone, doxycycline, griseofulvin, hydantoin, hydralazine, infliximab, interferon alpha, levamisole, minocycline combined with dianette, polyinosinic-polycytidylic acid, procainamide, thiamazole combined with propylthiouracil, topiramate, trimethadione, and zafirlukast. In 3 cases, the offending drug was not identified. The duration of these individuals' drug exposure was (0.2 to 150 months, median of 9 months). The clinical manifestations of their disorder which were observed in more than 1 patient were: fever (in 50.8% of cases), arthralgia (47.7%), rash (46.2%), arthritis (44.6%), malar rash (23.1%), proteinuria (20.%), lymphadenopathy (16.9%), myalgia (15.4%), weight loss (12.3%), anemia (9.2%), edema of the extremities and face (9.2%), fatigue (9.2%), lupus nephritis (9.2%), nausea (9.2%), pleural effusions (9.2%), headaches 5 (7.7%), hepatosplenomegaly or just splenomegaly (7.7%), malaise (7.7%), joint stiffness felt when awakening from sleep (7.7%), chest pain (6.1%), hematuria (6.1%), leukopenia (6.1%), myocarditis and/or pericarditis (6.1%), pneumonia (6.1%), generalized weakness (6.1%), oral ulcers, (6.1%), abdominal pain (4.6%), reductions in the number of almost all blood cells termed pancytopenia (4.6%), photosensitivity (4.6%), respiratory distress (4.6%), thrombocytopenia (4.6%), and hepatitis (3.1%).

Studies have reported that: vitamin D deficiency often occurs in patients with aSLE; vitamin D levels are particularly low in patients with more active aSLE;^[50][51] and aSLE patients treated with vitamin D have significant reductions in the activity of their disease.^[52] 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.^[53] 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).^[54] 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.^[54][55] 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,^[53] and reduced ability to suppress tissue inflammatory reactions.^[53][56][57] 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").^[53][58]

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.^[2] The Systemic Lupus International Collaborating Clinics (SLICC) is an international group dedicated to studying SLE. This group evaluated the following Clinical and Immunological criteria (i.e., immunological biomarkers) for diagnosing SLE. The group concluded that patients satisfying 4 of the 16 criteria listed below including at least one of the 10 Clinical criterium and one of the 6 Immunologic criterion had on their initial evaluation a sensitivity (i.e., probability of a positive test result conditioned on the individual truly being positive) of 82.7% and a specificity (i.e., probability of a negative test result, conditioned on the individual truly being negative) of 93.5% for cSLE. These two respective values for aSLE were 94% and 92%. Patients satisfying these criteria were therefore diagnosed as having cSLE or aSLE.^[59][60] For further details on these criteria see Fonseca, AR et al.^[59] and Petri, M et al.^[60]

Clinical criteria: Individuals exhibiting 1) lesions that occur in acute cutaneous lupus erythematosus such as a malar rash, toxic epidermal necrolysis, bullae, (i.e., large blisters containing serous fluid), maculopapular rashes, photosensitive lupus-like rashes (in individuals who do not have dermatomyositis), or subacute cutaneous lupus erythematosus-like lesions, e.g., scar-like polycyclic annular or plaque-like lesions on the skin most commonly in areas exposed to sunlight; 2) clinical signs found in discoid lupus erythematosus (with or without signs found in lichen planus) such as verrucous lupus erythematosus, lupus erythematosus panniculitis, mucosal lupus (i.e., lupus lesions involving mucous membrane), lupus erythematosus tumidus, or chilblain lupus erythematosus; 3) oral ulcers, i.e., ulcers on the mucous membranes of the nose, palate, tongue, and/or gums (in the absence of other causes such as vasculitis, Behçet's disease, Herpes infection, inflammatory bowel disease, reactive arthritis, or the excessive intake of acidic foods); 4) nonscarring alopecia, i.e., diffuse hair thinning or fragility with visibly broken hairs (in the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia; 5) synovitis involving two or more joints plus 30 minutes or more of morning joint stiffness; 6) pleurisy lasting more than one day, a pleural effusion or a pleural rub, serositis of the heart as shown by symptoms of pericardial pain that lasts for more than one day and is lessened by sitting forward, pericardial effusion, pericardial friction rub, or EKG evidence of pericarditis (in the absence of other causes such as infection, uremia, or Dressler's syndrome); 7) kidney dysfunction as indicated by a 24-hour urine protein of at least 500 milligram (i.e., mg) or the presence of red blood cell casts; 8) neurologic disorders such as seizures, psychosis, mononeuritis multiplex (in the absence of other causes such as primary vasculitis), myelitis, neuropathy in the peripheral or cranial nerves (not due to other causes such as primary vasculitis, infection, or diabetes mellitus), and acute mental confusion (in the absence of other causes such as toxic encephalopathy, uremia, or drugs); 9) hemolytic anemia; and 10) leukopenia with blood leukocyte levels less than 4,0000 per cubic millimeter occurring at least once (in the absence of other known causes such as Felty's syndrome, drugs, or portal hypertension), lymphopenia with blood lymphocyte counts less than 1000 per cubic millimeter (in the absence of other known causes such as drugs and infection), or thrombocytopenia with blood platelet counts less than 100,000/ per cubic milliliter (in the absence of other known causes such as drugs, portal hypertension, or thrombotic thrombocytopenic purpura).

Immunological criteria: Individuals exhibiting 1) high serum levels of antinuclear antibodies; 2) high serum levels of anti-dsDNA antibodies; 3) high serum levels of anti-Sm antibodies; 4) high blood levels of antiphospholipid antibodies, high blood levels of the lupus anticoagulant, a false positive rapid plasma reagin test, or a medium to high titer of IgA, IgG or IgM anti-cardiolipin or anti-β2 glycoprotein I-dependent anti-cardiolipin antibodies; 5) low serum levels of complement C3, complement C4, or total complement activity as measure by the CH50 test; and 6) a positive direct Coombs test in the absence of hemolytic anemia.

The SLICC also defined individuals with biopsy-proven lupus nephritis plus elevated blood levels of antinuclear and/or anti-dsDNA antibodies as having aSLE^[60] or cSLE.^[59]

In 2020, the European League Against Rheumatism (now named the European Alliance of Associations for Rheumatology) in collaboration with the American College of Rheumatology^[61] 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^[62] 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.^[61][63]

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).^[2][59][60] It is likely that a least some of the gene mutations causing aSLE not yet known to cause cSLE will be found to cause cSLE and therefore be regarded as diagnostic of cSLE.

The diagnose of cSLE is suggested in individuals with any symptoms of cSLE who have: a) one or more family members with a history of having SLE; b) mutations in genes that must interact with other genes to cause SLE (see above section on Genetics);^[6][35] or c) detectable blood and/or blood leukocyte levels of the mRNA for genes activated by the type-1 interferons, e.g., the EPSTI1, IFI44L, LY6E, OAS3, RSAD2 and sialoadhesin genes (the gene for sialoadhesin is termed SIGLEC-1).^[5][64] The abnormal presence of these mRNAs in tissues is sometimes termed the "interferon signature" or "high interferon signature".^[64] These interferon signature mRNAs have been detected in up to 90-95% of individuals with cSLE.^[5][9][65]