Summary
Some complement deficiencies predispose to SLE early in life. Currently, there are no known unique physiological or genetic pathways that can explain the variability in disease phenotypes, as is suggested by studies directly and indirectly comparing cohorts of children and adults with SLE. Children present with more acute illness and have more frequent renal, hematologic and central nervous system involvement at the time of diagnosis compared to adults with SLE. Almost all children require corticosteroids during the course of their disease, and many are treated with immunosuppressive drugs. Despite of a general lack of co-morbid conditions, mortality rates remain higher with pediatric SLE compared to aSLE. Children and adolescents accrue more damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, especially in the renal, ocular and musculoskeletal organ systems. Conversely, cardiovascular mortality is more prevalent in adults with SLE.
Keywords: Pediatric SLE, children, lupus, adults, lupus nephritis, complement
Introduction
An estimated 10 to 20% of patients experience the onset of SLE prior to adulthood. More precise estimates are difficult due to a lack of a clear age limit for the diagnosis of pediatric SLE. The maximum age at diagnosis most commonly used to define pediatric SLE is 16 years but ages range from 14 to 20 years in various studies1–8. This review article explores the differences and similarities of pediatric SLE and aSLE, preferably using studies that provide a direct comparison between groups. Issues pertaining to neonatal SLE are not addressed.
Gender Ratio & Disease Onset
Albeit uncommon, onset of pediatric SLE is described even in children younger than 2 years of age9. The female to male ratio with pediatric SLE changes from 4:3 with disease onset during the first decade of life to 4:1 during the second decade to 9:1 in aSLE, and decreases to 5:1 in SLE commencing after the age of 50 years10–13.
Pediatric SLE often presents with more acute and severe disease features than aSLE based on studies providing direct comparisons2, 8, 14. Almost all published research suggests a higher frequency of renal, neurological, and hematological involvement with pediatric SLE than with aSLE at the time of diagnosis2, 5–8, 15. In a Canadian inception cohort of 67 pediatric SLE patients the average disease activity score, as measured by the SLE Disease Activity Index (SLEDAI), was 16.8 at diagnosis but only 9.3 in the comparison group of 131 patients with aSLE (p = 0.0001)1. The most pronounced differences in disease activity between aSLE and pediatric SLE pertain to the renal or neurological organ systems16.
Despite widely variable estimates, fever and lymphadenopathy are more frequently described with pediatric SLE than aSLE in studies directly comparing both groups (see Table 1). Conversely, adults with SLE more commonly present with arthritis than children with SLE2, 4, 17. When comparing pre-pubertal to post-pubertal onset of pediatric SLE, the former group presents more often with hemolytic anemia and renal involvement whereas in the latter group cutaneous and musculoskeletal features are more common at disease onset9, 18. As with aSLE, about one third of the children and adolescents with SLE present with anemia, thrombocytopenia, or lymphopenia at the time of SLE onset19–21. On the contrary, leukopenia is more common in pediatric SLE than aSLE at onset (31 to 35% vs. 18%)19–20, 22, and 49% of children with SLE as compared to 18 to 65% of aSLE patients will test Coombs’ positive at the time of diagnosis19, 21, 23. Equally frequent in pediatric SLE and aSLE at the time of initial presentation (5 to 20%) are anti-Smith, anti-ribonucleoprotein, anti-Ro, and anti-La antibodies as is suggested by one study2.
Table 1.
Clinical and Laboratory Features in Pediatric SLE (pedSLE) and Adult SLE (aSLE) at Disease Onset ¶
| Study | Carreno 1999 a | Font 1998 b | ||||
|---|---|---|---|---|---|---|
| Clinical findings | pedSLE n=49 |
aSLE n=130 |
p-value | pedSLE n=34 |
aSLE n=396 |
p-value |
| Fever | 20 | 15 | NS | 41 | 21 | 0.006 |
| Lymphadenopathy | --‡ | -- | -- | 6 | 0.5 | 0.03 |
| Malar rash | 22 | 16 | NS | 44 | 35 | NS |
| Discoid lupus | -- | -- | -- | 0 | 3 | NS |
| Subcutaneous cutaneous lupus | -- | -- | -- | 0 | 3 | NS |
| Livedo reticularis | -- | -- | -- | 3 | 0.5 | NS |
| Oral ulcers | -- | -- | -- | 9 | 13 | NS |
| Photosensitivity | -- | -- | -- | 23 | 20 | NS |
| Arthritis | 22 | 39 | <0.05 | 65 | 62 | NS |
| Arthalgias | 26 | 23 | NS | -- | -- | -- |
| Myositis | -- | -- | -- | 3 | 4 | NS |
| Nephropathy | -- | -- | -- | 20 | 9 | 0.04 |
| Neurological involvement | -- | -- | -- | 0 | 6 | NS |
| Chorea | -- | -- | -- | 3 | 0 | NS |
| Serositis | -- | -- | -- | 12 | 13 | NS |
| Pleuritis | 6 | 6 | NS | -- | -- | -- |
| Lung involvement | -- | -- | -- | 0 | 1 | NS |
| Hemolytic anemia | -- | -- | -- | 9 | 3 | NS |
| Thrombocytopenia | -- | -- | -- | 12 | 9 | NS |
| Vasculitis | 8 | 2 | NS | -- | -- | -- |
| Cutaneous vasculitis | -- | -- | -- | -- | -- | -- |
| Raynaud’s phenomenon | 8 | 8 | NS | 12 | 16 | NS |
| Thrombosis | -- | -- | -- | 0 | 1 | NS |
| Sicca Syndrome | -- | -- | -- | 0 | 0.5 | NS |
Carreno L, Lopez-Longo FJ, Monteagudo I, et al. Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus. Lupus. 1999;8(4):287–92.
Font J, Cervera R, Espinosa G, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis. 1998 Aug;57(8):456–9.
Values expressed as percentages (%)
NS statistically not significant
-- no data in original article
Disease Course
Besides significantly more active disease at the time of disease onset, there is also more active disease over time with pediatric SLE when compared to aSLE1, 8. In the Canadian study previously mentioned, the average time-adjusted mean SLEDAI score was 5.7 with pediatric SLE but only 4.6 with aSLE (p= 0.012)1. Similarly, there was a trend towards more active disease during the course of the disease in adolescent-onset SLE patients (SLE onset between age 13 and 18 years) recruited to the Lupus in Minorities (LUMINA) study than in those with aSLE8.
At least five contemporary cohorts provide a direct comparison of disease features and laboratory abnormalities with pediatric SLE and aSLE over time. Specific details are presented in Table 2 and Table 32, 4–5, 17, 24. The variability in the estimates between studies may be a reflection of sample sizes or recruitment criteria but true divergence of SLE features due to race, ethnicity, specific environmental or health milieus are likely important as well. For this review we excluded some earlier studies that compared pediatric SLE to historic aSLE cohorts or research not designed to allow for the delineation of statistically significant differences between the groups7, 25.
Table 2.
Clinical Features in Pediatric SLE (pedSLE) and Adult SLE (aSLE) Over Time ¶
| Study | Hoffman 2009 a | Ramirez-Gomez 2008 b | Rood 1999 c | Carreno 1999 d | Font 1998 e | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Organ systems | pedSLE n=56 |
aSLE n=194 |
p-value | pedSLE n=230 |
aSLE n=984 |
p-value | pedSLE n=31 |
aSLE n=135 |
p-value | pedSLE n=49 |
aSLE n=130 |
p-value | pedSLE n=34 |
aSLE n=396 |
p-value |
| Constitutional | |||||||||||||||
| Fever | 67.3 | 51 | <0.05 | 63.5 | 55.2 | 0.02 | -- ‡ | -- | -- | -- | -- | -- | 62 | 43 | NS † |
| Fatigue | 78.6 | 83.5 | NS | -- | -- | -- | 87 | -- | -- | -- | -- | -- | -- | -- | -- |
| Weight loss | -- | -- | -- | -- | -- | -- | 71 | -- | -- | -- | -- | -- | -- | -- | -- |
| Lymphadenopathy | -- | -- | -- | -- | -- | -- | 36 | -- | -- | -- | -- | -- | 6 | 1 | NS |
| Mucocutaneous | |||||||||||||||
| Malar rash | 69.6 | 58.6 | NS | 70.4 | 59.1 | 0.002 | 71 | 40 | <0.05 | 59.1 | 59.2 | NS | 79 | 51 | 0.002 |
| Discoid lupus | 18.9 | 28.4∫ | NS | 12.6 | 11.6 | NS | 10 | 27 | <0.05 | 26.5 | 13.8 | <0.05 | 15 | 4 | NS |
| Subcutaneous cutaneous lupus | 9.6 | 2.2 | <0.05 | -- | -- | -- | -- | -- | -- | -- | -- | -- | 3 | 6 | NS |
| Alopecia | 41.1 | 45.1 | NS | -- | -- | -- | 48 | -- | -- | -- | -- | -- | -- | -- | -- |
| Generalized erythema | 20 | 9.5 | <0.05 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Livedo reticularis | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | 6 | 1 | NS |
| Oral ulcers | 28.6 | 23.5 | NS | 49.1 | 39.9 | 0.01 | 48 | 42 | NS | 40.8 | 37.6 | NS | 38 | 25 | NS |
| Genital ulcers | 3.6 | 4.3 | NS | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Photosensitivity | 44.6 | 53.2 | NS | 53 | 56.8 | NS | 39 | 43 | NS | 40.8 | 50.7 | NS | 44 | 35 | NS |
| Musculoskeletal | |||||||||||||||
| Articular manifestations | -- | -- | -- | -- | -- | -- | -- | -- | -- | 85.7 | 96.1 | <0.05 | -- | -- | -- |
| Arthritis | 59.3 | 66.8 | NS | 83 | 82 | NS | 100 | 94 | NS | -- | -- | -- | 88 | 81 | NS |
| Arthralgia | 75 | 98.7 | <0.005 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Myalgias | 42.4 | 35.2 | NS | 11.7 | 18.9 | 0.01 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Myositis | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | 3 | 7 | NS |
| Renal | |||||||||||||||
| Proteinuria | 63.6 | 4.2 | <0.01 | 49.1 | 45.3 | NS | 61 | 43 | NS | -- | -- | -- | -- | -- | -- |
| Urinary cell casts | 57.1 | 32 | <0.001 | -- | -- | -- | 65 | 53 | NS | -- | -- | -- | -- | -- | -- |
| Nephropathy | 62.5 | 36 | <0.001 | -- | -- | -- | -- | -- | -- | 67.3 | 48.4 | <0.05 | 50 | 34 | NS |
| Neuropsychiatric | |||||||||||||||
| Chorea | -- | -- | -- | 2.2 | 0 | 0.000 | -- | -- | -- | -- | -- | -- | 9 | 0 | <0.0 01 |
| Seizures | 14.5 | 6.9 | NS | 11.3 | 7.4 | 0.05 | 26 | 14 | NS | -- | -- | -- | -- | -- | -- |
| Cerebrovascular accident | 5.6 | 6.9 | NS | 5.2 | 2.2 | 0.01 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Transient ischemic attack | -- | -- | -- | 0.9 | 0 | 0.03 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Cranial nerve abnormalities | -- | -- | -- | 1.3 | 42 | 0.03 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Pseudotumor cerebri | -- | -- | -- | 0.9 | 0 | 0 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Headache | 25.5 | 30.9 | NS | -- | -- | -- | 61 | -- | -- | -- | -- | -- | -- | -- | -- |
| Concentration disorder | 20.4 | 17.8 | NS | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Psychosis | 9.3 | 5.9 | NS | 4.8 | 3.9 | NS | 13 | 6 | NS | -- | -- | -- | -- | -- | -- |
| Depression | 12.7 | 15.8 | NS | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Encephalopathy | 20.4 | 5.3 | <0.005 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Neurologic disorder | -- | -- | -- | -- | -- | -- | -- | -- | -- | 36.7 | 20 | <0.05 | -- | -- | -- |
| Cardiopulmonary | |||||||||||||||
| Pericarditis | 16.7 | 18.2 | NS | 17.0 | 17.3 | NS | 26 | 33 | NS | 16.3 | 13 | NS | -- | -- | -- |
| Serositis | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | 32 | 27 | NS |
| Pleuritis | 18.5 | 32.1 | NS | 17.4 | 23.2 | NS | 48 | 58 | NS | 28.5 | 33 | NS | -- | -- | -- |
| Pneumonitis | -- | -- | -- | -- | -- | -- | 10 | -- | -- | -- | -- | -- | -- | -- | -- |
| Lung involvement | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | 6 | 4 | NS |
| Miscellaneous | |||||||||||||||
| Thrombosis | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | 0 | 8 | NS |
| Raynaud’s phenomenon | 39.3 | 41.1 | NS | -- | -- | -- | 26 | -- | -- | 36.7 | 34.6 | NS | 20 | 25 | NS |
| Chillblains | 9.4 | 1.1 | <0.01 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Cutaneous vasculitis | -- | -- | -- | -- | -- | -- | -- | -- | -- | 44.8 | 27.6 | <0.05 | -- | -- | -- |
| Sicca Syndrome | -- | -- | -- | 3.9 | 9.3 | 0.007 | -- | -- | -- | -- | -- | -- | 9 | 15 | NS |
| Xerophthalmia | 3.8 | 18.7 | <0.01 | 1.7 | 6.6 | 0.004 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Xerostomia | 7.5 | 21.4 | <0.05 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
Hoffman IE, Lauwerys BR, De Keyser F, et al. Juvenile-onset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus. Ann Rheum Dis. 2009 Mar;68(3):412–5.
Ramirez Gomez LA, Uribe Uribe O, Osio Uribe O, et al. Childhood systemic lupus erythematosus in Latin America. The GLADEL experience in 230 children. Lupus. 2008;17(6):596–604.
Rood MJ, ten Cate R, van Suijlekom-Smit LW, et al. Childhood-onset Systemic Lupus Erythematosus: clinical presentation and prognosis in 31 patients. Scand J Rheumatol. 1999;28(4):222–6.
Carreno L, Lopez-Longo FJ, Monteagudo I, et al. Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus. Lupus. 1999;8(4):287–92.
Font J, Cervera R, Espinosa G, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis. 1998 Aug;57(8):456–9.
localized and disseminated discoid lesions
For legend please see legend Table 1
Table 3.
Laboratory Findings in Pediatric SLE (pedSLE) and Adult SLE (aSLE) Over Time ¶
| Study | Hoffman 2009 a | Ramirez-Gomez 2008 b | Rood 1999 c | Carreno 1999 d | Font 1998 e | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Laboratory test | pedSLE n=56 |
aSLE n=194 |
p-value | pedSLE n=230 |
aSLE n=984 |
p-value | pedSLE n=31 |
aSLE n=135 |
p-value | pedSLE n=49 |
aSLE n=130 |
p-value | pedSLE n=34 |
aSLE n=396 |
p-value |
| Antibodies | |||||||||||||||
| Antinuclear AB* | --‡ | -- | -- | 96.9 | 98.2 | NS† | 100 | 99 | NS | 100 | 99.2 | NS | -- | -- | -- |
| Anti-ds DNA AB | 60.7 | 24.9 | <0.001 | 67 | 71.3 | NS | 93 | 66 | <0.05 | 89.7 | 78.4 | NS | -- | -- | -- |
| Anti-Smith AB | 17.9 | 12.4 | NS | 51.3 | 47.6 | NS | 30 | 32 | NS | 20.4 | 14.6 | NS | -- | -- | -- |
| Anti-Ro AB | 23.2 | 33.5 | NS | -- | -- | -- | -- | -- | -- | 36.7 | 38.4 | NS | -- | -- | -- |
| Anti-La AB | 7.1 | 17.0 | NS | -- | -- | -- | -- | -- | -- | 12.2 | 13 | NS | -- | -- | -- |
| Anti-ribonucleoprotein AB | 14.3 | 17.5 | NS | -- | -- | -- | -- | -- | -- | 38.7 | 41.5 | NS | -- | -- | -- |
| Anti-ribosomal P AB | 25 | 11.3 | <0.001 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Anti-histone AB | 39.3 | 25.8 | <0.05 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Rheumatoid factor | -- | -- | -- | -- | -- | -- | 54 | -- | -- | 24.4 | 31.5 | NS | -- | -- | -- |
| Antiphospholipid AB | |||||||||||||||
| IgM aCL** AB | -- | -- | -- | 47.5 | 36.8 | 0.05 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| IgG aCL AB | -- | -- | -- | 51.8 | 50.2 | NS | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Lupus anticoagulant | -- | -- | -- | 34.4 | 29.6 | NS | 23 | -- | -- | -- | -- | -- | -- | -- | -- |
| Hematology | |||||||||||||||
| Anemia | -- | -- | -- | -- | -- | -- | 84 | 56 | <0.05 | -- | -- | -- | -- | -- | -- |
| Hemolytic anemia | 38.5 | 13 | <0.001 | 16.1 | 10.8 | 0.02 | -- | -- | -- | 20.4 | 10 | NS | 15 | 6 | NS |
| Leukocytopenia | 63.6 | 56.8 | NS | 46.1 | 41.5 | NS | 74 | 50 | <0.05 | 55.1 | 56.9 | NS | -- | -- | -- |
| Lymphopenia | 67.9 | 64.1 | NS | 60.4 | 59 | NS | 30 | 26 | NS | 30.6 | 21.4 | NS | -- | -- | -- |
| Thrombocytopenia | 31.5 | 25 | NS | 25.2 | 17.8 | 0.01 | 48 | 36 | NS | 30.6 | 38.4 | NS | 26 | 23 | NS |
Hoffman IE, Lauwerys BR, De Keyser F, et al. Juvenile-onset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus. Ann Rheum Dis. 2009 Mar;68(3):412–5.
Ramirez Gomez LA, Uribe Uribe O, Osio Uribe O, et al. Childhood systemic lupus erythematosus in Latin America. The GLADEL experience in 230 children. Lupus. 2008;17(6):596–604.
Rood MJ, ten Cate R, van Suijlekom-Smit LW, et al. Childhood-onset Systemic Lupus Erythematosus: clinical presentation and prognosis in 31 patients. Scand J Rheumatol. 1999;28(4):222–6.
Carreno L, Lopez-Longo FJ, Monteagudo I, et al. Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus. Lupus. 1999;8(4):287–92.
Font J, Cervera R, Espinosa G, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis. 1998 Aug;57(8):456–9.
AB Antibodies
aCL anti-cardiolipin
For legend please see legend Table 1
Mucocutaneous and Musculoskeletal Manifestations
When directly comparing pediatric SLE to aSLE inflammatory rashes, including the typical malar erythema, are significantly more frequent in children than adults2, 5, 24. Exceptions are photosensitivity and discoid skin lesions which are more prominently found with aSLE. Indeed, isolated discoid lupus erythematosus (DLE) is uncommon in childhood, with less than 5% of all DLE cases reported in patients under the age of 15 years2, 26. Lesions of DLE in children are indistinguishable from those in adults but children with DLE suffer less often from photosensitivity, and there is a less pronounced female predominance. Conversely, children with DLE more often have a positive family history of DLE or SLE and, more importantly, 25 to 30% of the children with DLE will progress to SLE as opposed to only 5 to 10% of adults26–27.
Painful non-erosive arthritis and arthralgias are common in both aSLE and pediatric SLE. There may be a trend towards more overt arthritis with pediatric SLE, while arthralgias and myalgias appear to be more frequently encountered in aSLE2, 4–5, 24. Whether differences in the frequencies of subjective musculoskeletal features between groups are related to the underlying disease or are a reflection of more common joint symptoms in adulthood remains to be determined. Jaccoud’s arthropathy28 and drug-induced myopathy, however, are more often described with aSLE29–30.
With a reported prevalence of about 40%, osteopenia (z-scores less than −1 or −1.5) is quite common in pediatric SLE, and osteoporotic fractures occur in 6% to 10% of the children31–32. This compares to reports of osteopenia at 40% and osteoporosis at 5% in premenopausal women with aSLE; much higher estimates are provided for aSLE cohorts that include post-menopausal patients33–34.
Traditional risk factors for osteoporosis that contribute to impaired bone health in aSLE are unlikely important in pediatric SLE35. Possibly due to inflammation, corticosteroid use, reduced physical activity, inadequate sun exposure, and low calcium and vitamin D intake, children and adolescents with SLE are often unable to reach their peak bone mass103,130,199. For reasons not fully understood, there is a higher prevalence of vitamin D deficiency in children and adults with SLE as compared to the general population36.
Lupus Nephritis
Lupus nephritis (LN) is often a presenting feature of pediatric SLE2. In comparative studies of pediatric SLE and aSLE, the prevalence of LN in adults with SLE is at 34 to 48%19, 24, 37. Despite large variations between racial groups, most studies report LN to be present in 50 to 67% of the children, at a higher frequency than with aSLE17, 19, 24, 37. Consequently, proteinuria and urinary cell casts during the disease course are more common with pediatric SLE than aSLE4. A study by Brunner et al. supports a similar distribution of LN histological classes in pediatric SLE as compared to aSLE1, with diffuse proliferative LN (Class IV) occurring in 40 to 60%, focal proliferative LN (Class III) in 10 to 20%, and membranous LN (Class V) in 3 to 28% of pediatric SLE patients with renal disease38. Overlap between proliferative and membranous changes are reported in 12% of the cases on initial kidney biopsy38. Hypertension occurs in 40% of pediatric SLE patients with LN3, 8, 39–40, and African-American children, particularly boys, may have a significantly higher risk of hypertension than Caucasians.
Neuropsychiatric SLE
Lack of specific laboratory tests and imaging modalities make the diagnostic process of neuropsychiatric involvement with SLE (NPSLE) difficult in children and adults with SLE. The types of NPSLE syndromes are similar in pediatric SLE and aSLE41–42.
NPSLE is at least as common in children as it is in adults43–46. Within the first year post diagnosis, 70% of the children, as compared to only 28% of adults, develop features compatible with NPSLE47–48. Depression is the most common mood disorder in children and adults without apparent differences in prevalence between groups4, 41–42. The Grupo Latino Americano de Estudio del Lupus (GLADEL) cohort reported a significantly higher prevalence of pseudotumor cerebri, transient ischemic attack, and seizures in their pediatric SLE cohort when directly compared with aSLE8. Despite a general lack of comorbid conditions, cerebrovascular disease is reported in up to 25% of children with NPSLE, and may be more common than in aSLE4, 24. Approximately 20% of children with NPSLE will develop psychosis which usually presents with visual hallucinations45, 49. Psychosis, chorea, or any type of encephalopathy occurs preferentially with pediatric SLE2, 8, 44, 50. Cerebral vein thrombosis is reported in 15 to 25% of the children with SLE, often presenting with severe headache in lupus anticoagulant (LAC) positive patients51. Conversely, cranial nerve abnormalities are more frequently encountered in aSLE than pediatric SLE8.
Neurocognitive dysfunction is reported in as many as 30 to 60% of all children with SLE 43–45, 52. This wide range of numeric estimates reported in the literature is likely due to differences in design and case ascertainment between studies. Nonetheless, neurocognitive dysfunction appears to be similarly widespread among children and adults with SLE16. The 1999 ACR case definitions of NPSLE have not been validated for use in children and adolescents, and the proposed 1-hour ACR battery of standardized tests to assess neuropsychiatric function is not suited for use in pediatrics53. More recently an alternative battery for children has been developed54.
Cardiopulmonary & Gastrointestinal Involvement
Pericarditis is the most commonly diagnosed cardiac manifestation of SLE and presents in about 17 to 33 % of SLE patients, irrespective of age55. Symptomatic coronary artery disease and myocardial infarction are both exceedingly rare in children and adolescents with SLE56. Conversely, clinically recognizable coronary artery disease is reported in 6 to 9% of adults with SLE, and ischemic heart disease remains a major factor for morbidity and mortality in aSLE57–58. Symptomatic and asymptomatic pulmonary manifestations are described in up to 60% of the children and adolescents with SLE59, which compares to estimates of 20 to 90% in aSLE60–61. In studies directly comparing children and adults with SLE, there is a trend towards more common occurrence of pleuritis with aSLE2, 4–5, 24. Among the most common pathological features reported in both pediatric SLE and aSLE are restrictive lung defects and impaired diffusion capacity62. Shrinking lung syndrome, e.g. restrictive lung disease combined with diaphragmatic paralysis, is a rare complication of SLE with less than 150 cases in adults and fewer than 10 cases reported in pediatrics63–64. Pulmonary hemorrhage is still linked to high mortality rates in children and adults with SLE 65.
The frequency of ascites in pediatric SLE is comparable to that in aSLE. Adults with SLE are commonly diagnosed with conventional age or medication related abdominal pathology66–67, while in children symptoms are more often due to SLE itself68. In a review of 175 adults hospitalized for aSLE, 22% presented with acute abdominal pain, which was due to aSLE in 44% of the cases67. Conversely, some abdominal pain was reported in 19% of 201 French children with SLE68. In this review in 87% of the cases the gastrointestinal pathology was attributed to pediatric SLE68.
Distinguishing surgical from non-surgical cases of acute abdomen is challenging, especially in children with SLE. Acute onset of even mild abdominal pain and low-grade fever in an otherwise well-controlled patient on immunosuppressive medications may be due to bacterial peritonitis. Abnormalities on ultrasound are present in about half of the children with SLE with abdominal pathology, while abnormalities on computer tomography are seen in 80% of the cases68.
Hematologic Manifestations
Chronic disease is the most common cause of anemia in both pediatric SLE and aSLE. There is a higher incidence of anemia in the very young, affecting 77% of patients with infantile SLE, i.e. SLE with onset prior to age one year, as compared to only 35% of children older than one year at onset of pediatric SLE9. Anemia in pediatric SLE is usually of a mild to moderate degree and normochromic normocytic but becomes microcytic and hypochromic over time43. Hemolytic anemia is more prevalent in pediatric SLE than aSLE as is suggested by several studies comparing pediatric SLE to aSLE2, 4, 24.
With a reported prevalence between 42 and 74% during the course of the disease, leukopenia occurs with similar frequency in pediatric SLE and aSLE4, 24. Leukopenia may be less frequent in young children with SLE as compared to pediatric SLE with onset at or after puberty9. Lymphopenia is as common with aSLE as it is with pediatric SLE over time. It changes with disease activity, is correlated with anti-double stranded DNA antibodies levels, and is associated with NPSLE and mucocutaneous involvement in pediatric SLE and aSLE69.
Neutropenia is similarly frequent in aSLE and pediatric SLE, occurring in about 12 to 15% of children and 4 to 20% of adults. Neutropenia has been associated with thrombocytopenia and NPSLE in both pediatric SLE and aSLE19, 70. Overall the prevalence of thrombocytopenia appears to be somewhat higher in pediatric SLE than aSLE4, 24. Thrombocytopenia occurs in about two thirds of children with infantile SLE and in 25 to 30% of pediatric SLE patients with disease onset later in life9. Low platelet counts are associated with the presence of antiphospholipid (aPL) and anti-platelet autoantibodies.
Prior to developing pediatric SLE, children and adults with thrombocytopenia may have carried a diagnosis of idiopathic thrombocytopenic purpura (ITP)71. In a study by Pamuk et al., six of 321 adults (2%) with ITP developed aSLE during a 4-year follow-up time72. In this cohort, 27% of the adult patients with ITP tested positive for antinuclear antibodies (ANA). In contrast, in a single retrospective study of 365 Turkish children with ITP, ANA titers of 1:80 or higher were present in 9% of the children but none developed pediatric SLE during the mean follow-up of 3.6 years73. However, given the low frequency of ANA positivity in the cohort, any potentially increased risk of ANA positive individuals to develop pediatric SLE might have been missed, and the observations from Turkey may not be typical for other parts of the world. In our experience, careful follow-up is warranted for any child with ITP who is found to have ANA at high titers.
Hemolytic uremic syndrome or thrombotic thrombocytopenic purpura (TTP) are rarely features of the initial presentation of pediatric SLE74–75. ANA positivity and high grade proteinuria at the time of presentation are both risk factors for children with TTP to subsequently develop pediatric SLE74. Based on a systematic review of the literature, at least 35% of children with TTP will subsequently develop pediatric SLE which compares to only 2 to 3 % among adults with TTP74, 76.
Although it has been described in all age groups, macrophage activation syndrome may be more common, or at least more recognized, in pediatric SLE than aSLE77–78. The morphologic features in the bone marrow of pediatric SLE and aSLE with macrophage activation syndrome are indistinguishable from those with other causes. Bone marrow dysplasia has been described in both pediatric SLE and aSLE79.
Antiphospholipid Antibody & Sjogren’s Syndromes
The prevalence of anti-cardiolipin (aCL) antibodies and LAC appears similar in groups of adults and children with SLE9. Thrombosis in patients who test positive for aPL antibodies is, however, more common in aSLE than pediatric SLE, likely reflective of underlying co-morbidities and longer disease duration in adults80. In a cross-sectional Canadian cohort study, children with SLE who tested persistently positive for LAC had a 28-fold increased risk of experiencing a thrombotic event compared to those without LAC81. About one third of pediatric SLE patients with aPL syndrome will experience recurrent thromboses within 13 months of the initial event, especially if anticoagulation is discontinued or when there are other predisposing thrombophilic factors81.
While 6.5% of all aSLE patients have Sjogren’s syndrome, it is less common in children with SLE (Table 2). Although a case series (n=34) from Japan reports that 41% of the children with SLE have secondary Sjogren’s syndrome, the prevalence of Sicca syndrome at 3.9% in pediatric SLE vs. 9.3% in aSLE was considerably lower in the much larger GLADEL cohort24, 82. Primary, as opposed to secondary Sjogren’s syndrome, is very rare prior to adulthood. In a cohort study of 180 children with primary pediatric Sjogren’s syndrome, the mean age at diagnosis was 9.8 years83. Common clinical manifestations of pediatric Sjogren’s syndrome are bilateral parotid swelling, which is present in 70% of the cases. Extraglandular manifestations were reported in 5% of the children in one series of patients with pediatric Sjogren’s syndrome. ANA positivity is less frequently observed in children than in adults with Sjogren’s syndrome84.
Endocrine Abnormalities
Types of endocrine aberrations are comparable in adults and children with SLE85. An estimated 50 to 85% of pediatric SLE and aSLE have dyslipidemia86–87. Pro-atherogenic lipid profiles in children and adults with SLE exist even prior to commencing steroid therapy86–88. Low density lipoprotein (LDL) particles are smaller with active compared to inactive disease in pediatric SLE and aSLE, contributing to their atherogenicity89–90. Compared to healthy controls, both adults and children with SLE have higher insulin levels which, if persistent, are associated with metabolic syndrome91–92. There may be higher rates of diabetes in aSLE compared to pediatric SLE1, 7.
Autoimmune thyroid disorders are associated with SLE and present in about 15 to 20% of the patients without apparent differences in prevalence between adults and children93–94.
There is a trend towards higher levels of follicle stimulating hormone, luteinizing hormone, and prolactin in cSLE patients compared to healthy children95–96. Elevated prolactin levels occur in subsets of pediatric SLE and aSLE patients with active disease, especially those with NPSLE96 , 97.
Menarche in females with pediatric SLE is, on average, delayed by one year. The delay in puberty progression increases with longer disease durations and the higher cumulative doses of corticosteroids used for treatment (R2> 0.3; p< 0.009)98. Transient or permanent amenorrhea has been reported in 12% of 298 adolescents with pediatric SLE and is positively correlated with both the presence of disease activity and damage. Ovarian failure is a well-known complication of intravenous cyclophosphamide therapy in aSLE. The risk of ovarian failure after cyclophosphamide is considerably lower in pediatric SLE than in aSLE99–100. Based on limited information from case series, the average risk of premature ovarian failure is 11% in females with pediatric SLE who are younger than 21 years of age98, 101–102. In a cohort of 77 patients with pediatric SLE, of whom 47% were treated with cyclophosphamide, a reduced ovarian reserve, but not overt ovarian failure, was observed in 31% of the females who were treated with cyclophosphamide102. Different from aSLE, ovarian protection has not been studied in pediatric SLE but a randomized trial of a gonadotropin-releasing hormone agonist is ongoing to assess the benefits and risks of transient ovarian suppression102.
As with aSLE, semen abnormalities, low testicular volumes, and high gonadotropin levels all appear to be more frequent in males with pediatric SLE than their healthy peers, especially following cyclophosphamide therapy with initiation after the onset of puberty103–104. Sertoli cell dysfunction is more common in pediatric SLE males than in healthy adolescents. Semen abnormalities are more common with immunosuppressive use, especially with cyclophosphamide104.
Immunological Features
As with aSLE, circulating ANA are the hallmark of pediatric SLE, and present in virtually all children105. An estimated 30 to 50% of children referred to pediatric rheumatologists who test ANA positive have a musculoskeletal pain syndrome and not pediatric SLE106. In a retrospective study of 110 children who tested positive for ANA, 10 children eventually developed pediatric SLE after follow-up of up to four years. The median ANA titer of the children who developed pediatric SLE was 1:1,080107, while ANA titers of 1:320 or lower appeared not to confer a sizeable risk for the subsequent development of pediatric SLE107.
Most studies that directly compare pediatric SLE to aSLE suggest that elevated levels of anti-double stranded DNA (anti-dsDNA) antibodies to be more common in pediatric SLE than in aSLE (61 to 93% vs. 25 to 78%)2, 4–5, 17, 24. An estimated 92% of children with infantile SLE test positive for anti-dsDNA antibodies9. As with aSLE, changes in the levels of anti-dsDNA antibodies are used to monitor disease activity in pediatric SLE108. There are conflicting reports as to whether anti-dsDNA antibodies and complement levels are predictive of future pediatric SLE or aSLE flares109. Although traditionally viewed to be specific to SLE, anti-dsDNA antibodies can be present with autoimmune hepatitis, Epstein Barr virus infections, rheumatoid arthritis, and very rarely, in healthy people110.
Besides anti-dsDNA antibodies, anti-histone and anti-ribosomal P antibodies are all more frequently encountered in pediatric SLE than aSLE4. Anti-ribosomal P antibodies are elevated in 25 to 42% of the patients with pediatric SLE4 compared to only 6 to 11% of the patients with aSLE4, 47, 111. One study directly comparing pediatric SLE and aSLE for the presence of anti-histone antibodies suggest a significantly higher prevalence in the former than the latter, 39% and 26% respectively4.
The prevalence of anti-Smith (Sm), anti-ribonucleoprotein (RNP), anti-Ro/SSA and anti-La/SSB antibodies appears not to differ between pediatric SLE and aSLE4. Anti-Sm antibodies are present in up to 51%, anti-RNP antibodies in about 37%, anti-Ro antibodies in 33%, and anti-La antibodies in 15% of pediatric SLE patients during the course of their disease, respectively2, 4–5, 16–17, 24. The disease association of the antibody clustering in pediatric SLE may be different from that observed in aSLE112. Similar to what has been reported in aSLE, there are ethnic variations in the frequency of auto-antibodies with pediatric SLE; anti-U1RNP and anti-Sm antibodies occur more frequently in non-Caucasian patients with pediatric SLE112–113. Despite a lack of comparative studies, the frequency of anti-nucleosome antibodies appears comparable in aSLE and pediatric SLE114–115. The Rheumatoid Factor (RF) is positive in 5% of the pediatric SLE patients at diagnosis and in 10 to 54% of them over time, exceeding the frequency at which RF is reported in Juvenile Idiopathic Arthritis2, 5, 7, 17. A comparative study of aSLE and pediatric SLE suggests a trend towards more common RF positivity among adults at both diagnosis and during the course of the disease2.
Genetics
There is limited knowledge about the relative risk of children of different races to develop SLE. However, as with aSLE, non-Caucasian children appear to be at a higher risk of being diagnosed with SLE. Genetic studies in pediatric SLE provide, for the most part, confirmation of genetic variants reported in aSLE and presently do not explain differences in disease presentation, activity, and outcomes between pediatric SLE and aSLE21, 116.
Congenital complement deficiencies are present in about 1% of patients with SLE117. The closest association between SLE and complement deficiencies is seen with C1q deficiency, where there is a risk of over 90% to develop a lupus-like illness early in life117–118. Deficiency of C1q is a rare condition with only about 50 cases reported in the literature. Other complement deficiencies include homozygous C4 deficiency with a 75% association rate with SLE119 and C1s or C1r deficiency which has a 50% association rate with SLE, again with onset early in life. Homozygous C2 deficiency is present in 1/10,000 to 1/30,000 Caucasians, and 10 to 30% of them may develop SLE117.
The Major Histocompatibility Complex (MHC) Class II and III alleles have long been implicated in conveying risk for developing SLE. HLA DRB1*15:03, DRB5*01:01, DQA1*01:02, DQB1*06:02 are more common in American Blacks with SLE, independent of age at disease onset120. HLA DRB1*03:01, DQA1*05:01, and DQB1*02:01 are more common in Caucasians with SLE, again independent of age at disease onset121. Non-MHC loci that have been associated with pediatric SLE and aSLE are the 1858T single nucleotide polymorphism (SNP) of PTPN22, a gene which encodes for the enzyme lymphocyte phosphatase (Lyp) and inhibits T-cell activation116, 122–123. A polymorphism (−28C/G polymorphism) of the RANTES (also CCL5) gene also has been associated with aSLE, and its importance was confirmed in a study of Chinese children with SLE124. A genome-wide scan in children and adults proposed that susceptibility to SLE is conveyed by the N673S polymorphism of the P-selectin gene (SELP), a cell adhesion molecule expressed on activated endothelial cells, and of the C203S polymorphism of the interleukin-1 receptor-associated kinase 1 gene (IRAK1), which is involved in the signaling cascade of the toll/interleukin-1 receptor family125. Another SNP, PD1.3G/A, located within the regulatory area of the programmed cell death 1 (PDCD1) gene, is also a proposed susceptibility locus of aSLE and pediatric SLE from Mexico126.
Therapy
Treatment approaches to pediatric SLE and aSLE vary across centers and are largely determined by organ involvement, disease activity and damage, access to medications, and institutional preferences18, 127. Comparative studies of adults and children support that pediatric SLE is more often treated with high doses of corticosteroids and immunosuppressive medications than aSLE (see Table 4). When comparing therapies of patients treated at two Canadian tertiary hospitals, children with SLE were more often prescribed oral corticosteroids than adults (97% of 67 pediatric SLE patients vs. 70% of 131 aSLE patients)1. In the same study, children with SLE were treated with intravenous methylprednisolone almost three times more often than adults1. This is similar to what has been reported from a cohorts of 90 pediatric SLE and 795 aSLE patients managed in the United States (U.S.)3, but no important differences in steroid use between aSLE and pediatric SLE were noted by others2, 8.
Table 4.
Medication Prescribed During Follow-up in Pediatric SLE (pedSLE) and Adult SLE (aSLE) ¶
| Study | Hersh 2009 a | Brunner 2008 b | Tucker 2008 c | Font 1998 d | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Medication | pedSLE n=90 |
aSLE n=795 |
p-value | pedSLE n=67 |
aSLE n=131 |
p-value | adoSLE¶¶ n=31 |
aSLE n=48 |
p-value | pedSLE n=34 |
pedSLE n=34 |
p-value |
| Traditional non- steroidal anti- inflammatory drugs |
81.8 | 88.1 | NS† | --‡ | -- | -- | -- | -- | -- | 88 | 81 | NS |
| COX-2 inhibitors | 23 | 49.9 | <0.001 | -- | -- | -- | -- | -- | -- | -- | -- | -- |
| Antimalarials | 87.6 | 83.8 | NS | 81 | 73 | NS | -- | -- | -- | 85 | 82 | NS |
| Oral corticosteroids | 100 | 89.3 | 0.001 | 97 | 70 | <0.0001 | 96.8 | 85.4 | NS | 94 | 84 | NS |
| Pulse methylprednisolone |
48.8 | 38.4 | 0.064 | 30 | 11 | 0.001 | -- | -- | -- | 3 | 1 | NS |
| Immunosuppressive medications |
-- | -- | -- | 66 | 37 | 0.0001 | -- | -- | -- | -- | -- | -- |
| Azathioprine | 33.7 | 28.4 | NS | 64 | 75 | NS | -- | -- | -- | 15 | 2 | 0.00004 |
| Methotrexate├ | 26.9 | 30.9 | NS | 9 | 31 | NS | -- | -- | -- | -- | -- | -- |
| Mycophenolate mofetil |
28.1 | 13 | <0.001 | 0 | 2 | NS | -- | -- | -- | -- | -- | -- |
| Cyclosporine | 18.6 | 9.9 | 0.014 | 2 | 0 | NS | -- | -- | -- | -- | -- | -- |
| Intravenous cyclophosphamide |
30.7 | 14.1 | <0.001 | 25 | 21 | 0.009 | 16.1 | 4.2 | NS | -- | -- | -- |
| Oral cyclophosphamide |
3.5 | 7.5 | NS | -- | -- | -- | -- | -- | -- | 9 | 4 | NS |
Hersh AO, von Scheven E, Yazdany J, et al. Differences in long-term disease activity and treatment of adult patients with childhood- and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2009 Jan 15;61(1):13–20.
Brunner HI, Gladman DD, Ibanez D, et al. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus.Arthritis Rheum. 2008 Feb;58(2):556–62.
Tucker LB, Uribe AG, Fernandez M, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII). Lupus. 2008;17(4):314–22.
Font J, Cervera R, Espinosa G, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis. 1998 Aug;57(8):456–9.
Values expressed as percentages (%)
adoSLE: The cohort pediatric SLE patients had disease onset between the ages 13 and 18 years
oral or injectable methotrexate
For legend please see legend Table 1
More frequent utilization of any immunosuppressive medication with pediatric SLE compared to aSLE is reported by several investigators1–3, 16, although the types of immunosuppressive drugs prescribed appear not to differ between children and adults, except for a more common use of methotrexate in aSLE than pediatric SLE (31% vs. 9%)1.
There is a trend towards a more frequent administration of intravenous cyclophosphamide in the adolescent-onset group compared to aSLE in the LUMINA cohort8. How the increasing use of rituximab in recent years has affected overall medication profiles in pediatric SLE and aSLE is unknown at this point.
Patients with SLE of all ages older than 6 years are equally likely to be prescribed antimalarials1, 3. Adults and children with SLE are comparable in their use of non-steroidal anti-inflammatory medications2–3, except for cyclooxygenase 2 inhibitors which appear to be less commonly prescribed to children and adolescents3.
Corticosteroids, intravenous immunoglobulins, dapsone, vincristine, and various immunosuppressive medications have all been used to treat SLE-associated thrombocytopenia in both children and adults. Successful therapy of chronic treatment-resistant hemolytic anemia and thrombocytopenia in pediatric SLE with rituximab is reported from a single center; no serious infections were observed, despite prolonged B-cell depletion128.
Children and adolescents with NPSLE appear to have an excellent response to treatment, and the majority of them will experience a resolution of symptoms. As with NPSLE in adults, high dose glucocorticoids, often combined with immunosuppressive medications including cyclophosphamide, are the mainstays of NPSLE treatment of children44, 129. For NPSLE-associated cerebral vein thrombosis or arterial strokes anti-coagulation is added to the anti-inflammatory drug regimen130. There are no longitudinal randomized studies addressing target parameters for anticoagulant therapy or anti-thrombotic prophylaxis in pediatric NPSLE. Academic delays of children and adolescents with NPSLE have not been quantified but are likely considerable. Educational interventions and psychological support appear important for children with NPSLE, based on studies in aSLE131.
Treatment of LN in pediatric SLE is adapted from protocols used in adults. As with aSLE the best induction and maintenance therapy for pediatric SLE-associated LN remains to be determined132–133. In children with severe LN cyclophosphamide use is associated with better renal survival compared to corticosteroids therapy alone134. Lehman et al. treated 16 patients with Class III or IV LN with monthly intravenous pulse cyclophosphamide for six months, followed by three monthly infusions for a total of 36 months. A significant reduction of proteinuria, disease activity, and prednisone dosage at one year post initial diagnosis was observed as well as improvement of LN on re-biopsy. No significant treatment complications were reported by this group during the 3-year study135. The combination therapy of cyclophosphamide and methotrexate for refractory Class IV therapy in children with SLE has been suggested but is rarely used in pediatric or adults clinical practice, given its potentially severe side effects136.
Different form aSLE, there are no randomized trials of mycophenolate mofetil for specifically pediatric SLE treatment. The efficacy and safety of mycophenolate mofetil in controlling LN in children has been reported: in a case series mycophenolate mofetil was effective in five of thirteen patients (38%), partially effective in four (31%), and ineffective in four (31%). No severe side-effects were observed137.
Some studies suggest that proliferative LN in children progresses in 9 to 15% of the cases to end-stage renal disease within 5 years38, 138, which is comparable to what has been reported from some aSLE cohorts139. LN accounts for 3% of end-stage renal disease leading to kidney transplantations among children in North America140, while adults with SLE account for 1.9% of the adult kidney transplant population, based on the U.S. Renal Data System.
A review of the North American Renal Transplant Cooperative Study database supports 1-year graft survival rates with pediatric SLE at 91% after living donor, and 78% after cadaveric transplants. This compares to estimates of graft survival in aSLE at 88% at one year, and 67% at five years. In both aSLE and pediatric SLE kidney graft survival is similar to that with other adult or pediatric diseases139, 141–142.
Prognosis and Survival
Delay in aSLE diagnosis is associated with higher mortality and a reduced likelihood of achieving remission143. In adults with SLE remission for 1-year is reported in as many as 6.5% of the patients144. Conversely, despite a lack of firm estimates, remission is exceedingly rare in pediatric SLE in North America3.
Historically, children and adolescents have higher mortality rates and are perceived to encounter more disease damage than adults with SLE1, 8. The 5-year survival rates have improved in pediatric SLE from 30–40% in 1950’s, to over 90% in the 1980’s145–147. Similarly survival has much improved with aSLE148. In both aSLE and pediatric SLE recent 5-year survival rates well over 90% are reported from developed countries149–152. Nevertheless, in the LUMINA cohort, there is an almost 2-fold higher mortality with adolescent-onset SLE than with aSLE (19.4% vs. 10.4%, p=0.37)24.
Major causes of death in pediatric SLE and aSLE include renal disease, severe disease flares, and infections146–147, 153–154. While NPSLE is a risk factor of poor outcome in pediatric SLE, cardiovascular disease remains an important cause of death in aSLE. There is an ongoing controversy as to whether age at SLE onset constitutes a risk factor for poor disease outcome (see Table 5)18, 39, 155. Male sex, Black race, low socioeconomic status, thrombocytopenia, disease damage, and non-adherence to treatment, have all been linked with worse survival149, 156–157. Non-adherence to visits and medications is a universal challenge for SLE patients of all ages. In a single center study, 39% of 55 adolescents and adults with SLE were non-adherent (adherence rates less than 80%) to prednisone and 51% to hydroxychloroquine, based on pharmacy refill data158. Significant risk factors of insufficient adherence included being single, low educational level, and presence of other comorbidities but not age at disease onset. Initial study suggests text messaging to be a promising venue to enhance adherence to pediatric SLE therapies159.
Table 5.
Damage Accrual in Pediatric SLE (pedSLE) and Adult SLE (aSLE) as measured by the SLICC/ACR Damage Index ¶
| Study | Brunner 2008 a | Tucker 2008 b | ||||
|---|---|---|---|---|---|---|
| Damage Domain | pedSLE n=66 |
aSLE n=131 |
p-value | adoSLE¶¶ n=31 |
aSLE n=48 |
p-value |
| SDI╞ Domains | ||||||
| Ocular | 42.2 | 13 | <0.0001 | 9.7 | 4.3 | NS |
| Neuropsychiatric | 12.1 | 9.9 | NS | 29 | 19.6 | NS |
| Renal | 9.1 | 6.1 | NS | 45.2 | 17.4 | 0.023 |
| Pulmonary | 3.0 | 2.3 | NS | 3.2 | 6.5 | NS |
| Cardiovascular | 1.5 | 4.6 | NS | 6.5 | 4.3 | NS |
| Peripheral vascular | 3.0 | 1.5 | NS | 0 | 8.7 | NS |
| Gastrointestinal | 3.0 | 2.3 | NS | 3.2 | 10.9 | NS |
| Musculoskeletal | 24.2 | 9.9 | 0.007 | 19.4 | 15.2 | NS |
| Integument | 7.6 | 6.9 | NS | 9.7 | 15.2 | NS |
| Gonadal | 0 | 1.5 | NS | 12.9 | 10.9 | NS |
| Diabetes | 3.0 | 4.6 | NS | 3.2 | 8.7 | NS |
| Malignancy | 0 | 3.8 | NS | 3.2 | 0 | NS |
| Mean (SD)╘ of SDI score at study entry | -- | -- | -- | 0.7 (1.1) | 0.5 (1.0) | NS |
| Mean (SD) in months of disease duration at study entry | 1.13 (5.01) | 2.83 (3.43) | 0.014 | 1.7 (1.5) | 1.6 (1.4) | NS |
| Mean (SD) of SDI score at the end of follow-up | 1.76 (2.67) | 0.76 (1.16) | 0.008 | 2.3 (2.5) | 1.6 (2.0) | NS |
| Mean (SD) in years of disease duration at the end of the study | 3.2 (2) | 3.5 (2.6) | NS | 5.1 (3.0) | 4.0 (2.8) | NS |
| Proportion¶ of patients with ANY damage as measured by the SDI | 56.1 | 43.5 | NS | 64.5 | 66.7 | NS |
Brunner HI, Gladman DD, Ibanez D, et al. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2008 Feb;58(2):556–62.
Tucker LB, Uribe AG, Fernandez M, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII). Lupus. 2008;17(4):314–22.
SDI: Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index
Values are percentages (%) of patients of the total group unless otherwise noted
adoSLE: The cohort pediatric SLE patients had disease onset between the ages 13 and 18 years
Standard deviation
For legend please see legend Table 1
Despite improved survival rates in SLE patients of all ages, there remains substantial morbidity due to disease damage160–161. In aSLE, increasing age and longer duration of disease are correlated with disease damage. About 50 to 70% of adults with SLE will have accrued some disease damage at 10 years post diagnosis149, 162. In a study of 1,015 pediatric SLE patients from 39 countries, 40% of the children acquired some disease damage during mean disease durations of four years. This percentage increased to 58% in those with disease durations of over five years163, with similar results reported by others16, 18.
Statistically significant differences in the development of damage between aSLE and pediatric SLE were noted in the past. Comparison of Canadian inception cohorts found children with SLE to have mean SLICC/ACR damage index scores of 1.7 and adults of 0.76, respectively1. Ocular and musculoskeletal damage were statistically more common in children but there was a trend towards higher rates of malignancy with aSLE (Table 5)1. In the LUMINA cohort there was a trend towards higher rates of any disease damage in the adolescent-onset group as compared to the aSLE group (mean SLICC/ACR damage index score at last available visit, 2.3 vs.1.6)8, and renal damage was significantly less frequent in those with disease onset in adulthood (p = 0.023). In the LUMINA cohort, patients with diagnosis during adolescence also had a trend towards more neuropsychiatric, ocular, and musculoskeletal damage but there were more diabetes and peripheral vascular damage in those with disease onset during adulthood8.
Cost of Care
Cost of care is considerably higher in children than adults with SLE164–165. The estimated economic burden of pediatric SLE ranges from $146 to $650 million annually in the U.S.164. In a study utilizing administrative databases from two tertiary pediatric rheumatology centers in the U.S., the annual cost of care of pediatric SLE was $14,944 (cost basis: 2000), excluding outpatient medication expenses. Cost was accrued mostly by hospitalizations (28%), laboratory testing (21%), and outpatient clinic visits (20%), while emergency department visits contributed to only 1% to the total cost of care. Renal replacement therapy, although required for only three of the 119 children, constituted 11% of the total cost. Previous studies examining the cost of health services in aSLE used a slightly different valuation system than that used for the above mentioned study in children. Nonetheless, using a conservative estimate, the direct cost of care for a child with SLE appears to be roughly three times higher than for an adult. Whether this difference in cost between adults and children is due to differences in health care delivery systems, adherence to therapies, or differences in disease severity remains to be determined166.
Acknowledgments
Support: Dr. Brunner is supported by NIAMS P60 AR47784. Dr Mina is supported by the NIH00 Trainings Grant T32 AR074594.
Footnotes
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Contributor Information
Rina Mina, Department of Pediatrics, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center; 3333 Burnet Avenue, MC 4010; Cincinnati, Ohio 45229; U.S.A. rina.mina@cchmc.org; Tel: 001-513-636-8092..
Hermine I Brunner, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center; 3333 Burnet Avenue, MC 4010; Cincinnati, Ohio 45229; U.S.A. hermine.brunner@cchmc.org; Tel: 001-513-636-7982..
Literature
- 1.Brunner HI, Gladman DD, Ibanez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2008 Feb;58(2):556–562. doi: 10.1002/art.23204. [DOI] [PubMed] [Google Scholar]
- 2.Font J, Cervera R, Espinosa G, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis. 1998 Aug;57(8):456–459. doi: 10.1136/ard.57.8.456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hersh AO, von Scheven E, Yazdany J, et al. Differences in long-term disease activity and treatment of adult patients with childhood- and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2009 Jan 15;61(1):13–20. doi: 10.1002/art.24091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hoffman IE, Lauwerys BR, De Keyser F, et al. Juvenile-onset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus. Ann Rheum Dis. 2009 Mar;68(3):412–415. doi: 10.1136/ard.2008.094813. [DOI] [PubMed] [Google Scholar]
- 5.Rood MJ, ten Cate R, van Suijlekom-Smit LW, et al. Childhood-onset Systemic Lupus Erythematosus: clinical presentation and prognosis in 31 patients. Scand J Rheumatol. 1999;28(4):222–226. doi: 10.1080/03009749950155580. [DOI] [PubMed] [Google Scholar]
- 6.Tucker LB. Making the diagnosis of systemic lupus erythematosus in children and adolescents. Lupus. 2007;16(8):546–549. doi: 10.1177/0961203307078068. [DOI] [PubMed] [Google Scholar]
- 7.Tucker LB, Menon S, Schaller JG, Isenberg DA. Adult- and childhood-onset systemic lupus erythematosus: a comparison of onset, clinical features, serology, and outcome. Br J Rheumatol. 1995 Sep;34(9):866–872. doi: 10.1093/rheumatology/34.9.866. [DOI] [PubMed] [Google Scholar]
- 8.Tucker LB, Uribe AG, Fernandez M, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII) Lupus. 2008;17(4):314–322. doi: 10.1177/0961203307087875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Pluchinotta FR, Schiavo B, Vittadello F, Martini G, Perilongo G, Zulian F. Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes. Lupus. 2007;16(8):550–555. doi: 10.1177/0961203307080636. [DOI] [PubMed] [Google Scholar]
- 10.Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006;15(5):308–318. doi: 10.1191/0961203306lu2305xx. [DOI] [PubMed] [Google Scholar]
- 11.Malleson PN, Fung MY, Rosenberg AM. The incidence of pediatric rheumatic diseases: results from the Canadian Pediatric Rheumatology Association Disease Registry. J Rheumatol. 1996 Nov;23(11):1981–1987. [PubMed] [Google Scholar]
- 12.Nossent HC. Systemic lupus erythematosus in the Arctic region of Norway. J Rheumatol. 2001 Mar;28(3):539–546. [PubMed] [Google Scholar]
- 13.McCarty DJ, Manzi S, Medsger TA, Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum. 1995 Sep;38(9):1260–1270. doi: 10.1002/art.1780380914. [DOI] [PubMed] [Google Scholar]
- 14.Tucker LBUA, Fernandez M. Clinical differences between juvenile and adult onset patients with systemic lupus erythematosus: results from a multiethnic longitudinal cohort. Arthritis Rheum. 2006;54(6):S162. [Google Scholar]
- 15.Costallat LT, Coimbra AM. Systemic lupus erythematosus: clinical and laboratory aspects related to age at disease onset. Clin Exp Rheumatol. 1994 Nov–Dec;12(6):603–607. [PubMed] [Google Scholar]
- 16.Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr. 2008 Apr;152(4):550–556. doi: 10.1016/j.jpeds.2007.09.019. [DOI] [PubMed] [Google Scholar]
- 17.Carreno L, Lopez-Longo FJ, Monteagudo I, et al. Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus. Lupus. 1999;8(4):287–292. doi: 10.1191/096120399678847786. [DOI] [PubMed] [Google Scholar]
- 18.Descloux E, Durieu I, Cochat P, et al. Paediatric systemic lupus erythematosus: prognostic impact of antiphospholipid antibodies. Rheumatology (Oxford) 2008 Feb;47(2):183–187. doi: 10.1093/rheumatology/kem335. [DOI] [PubMed] [Google Scholar]
- 19.Bader-Meunier B, Armengaud JB, Haddad E, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study. J Pediatr. 2005 May;146(5):648–653. doi: 10.1016/j.jpeds.2004.12.045. [DOI] [PubMed] [Google Scholar]
- 20.Iqbal S, Sher MR, Good RA, Cawkwell GD. Diversity in presenting manifestations of systemic lupus erythematosus in children. J Pediatr. 1999 Oct;135(4):500–505. doi: 10.1016/s0022-3476(99)70174-5. [DOI] [PubMed] [Google Scholar]
- 21.Hiraki L, Benseler S, Tyrrell P, Harvey E, Hebert D, Silverman E. Ethnic Differences in Pediatric Systemic Lupus Erythematosus. J Rheumatol published online before print. 2009 October 15; doi: 10.3899/jrheum.081141. doi:10.3899/jrheum.08114. [DOI] [PubMed] [Google Scholar]
- 22.Cooper GS, Parks CG, Treadwell EL, et al. Differences by race, sex and age in the clinical and immunologic features of recently diagnosed systemic lupus erythematosus patients in the southeastern United States. Lupus. 2002;11(3):161–167. doi: 10.1191/0961203302lu161oa. [DOI] [PubMed] [Google Scholar]
- 23.Gattorno M, Buoncompagni A, Molinari AC, et al. Antiphospholipid antibodies in paediatric systemic lupus erythematosus, juvenile chronic arthritis and overlap syndromes: SLE patients with both lupus anticoagulant and high-titre anticardiolipin antibodies are at risk for clinical manifestations related to the antiphospholipid syndrome. Br J Rheumatol. 1995 Sep;34(9):873–881. doi: 10.1093/rheumatology/34.9.873. [DOI] [PubMed] [Google Scholar]
- 24.Ramirez Gomez LA, Uribe Uribe O, Osio Uribe O, et al. Childhood systemic lupus erythematosus in Latin America. The GLADEL experience in 230 children. Lupus. 2008;17(6):596–604. doi: 10.1177/0961203307088006. [DOI] [PubMed] [Google Scholar]
- 25.Meislin AG, Rothfield N. Systemic lupus erythematosus in childhood. Analysis of 42 cases, with comparative data on 200 adult cases followed concurrently. Pediatrics. 1968 Jul;42(1):37–49. [PubMed] [Google Scholar]
- 26.Del Boz J, Martin T, Samaniego E, Vera A, Sanz A, Crespo V. Childhood discoid lupus in identical twins. Pediatr Dermatol. 2008 Nov–Dec;25(6):648–649. doi: 10.1111/j.1525-1470.2008.00794.x. [DOI] [PubMed] [Google Scholar]
- 27.Sampaio MC, de Oliveira ZN, Machado MC, dos Reis VM, Vilela MA. Discoid lupus erythematosus in children--a retrospective study of 34 patients. Pediatr Dermatol. 2008 Mar–Apr;25(2):163–167. doi: 10.1111/j.1525-1470.2008.00625.x. [DOI] [PubMed] [Google Scholar]
- 28.Santiago MB, Galvao V. Jaccoud arthropathy in systemic lupus erythematosus: analysis of clinical characteristics and review of the literature. Medicine (Baltimore) 2008 Jan;87(1):37–44. doi: 10.1097/MD.0b013e3181632d18. [DOI] [PubMed] [Google Scholar]
- 29.Nord JESP, Rinaldi RZ, Weisman MH. Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature. Semin Arthritis Rheum. 2004 Apr;33(5):336–351. doi: 10.1016/j.semarthrit.2003.09.012. [DOI] [PubMed] [Google Scholar]
- 30.Kanayama Y, Shiota K, Horiguchi T, Kato N, Ohe A, Inoue T. Correlation between steroid myopathy and serum lactic dehydrogenase in systemic lupus erythematosus. Arch Intern Med. 1981 Aug;141(9):1176–1179. [PubMed] [Google Scholar]
- 31.Alsufyani KA, Ortiz-Alvarez O, Cabral DA, et al. Bone mineral density in children and adolescents with systemic lupus erythematosus, juvenile dermatomyositis, and systemic vasculitis: relationship to disease duration, cumulative corticosteroid dose, calcium intake, and exercise. J Rheumatol. 2005 Apr;32(4):729–733. [PubMed] [Google Scholar]
- 32.Trapani S, Civinini R, Ermini M, Paci E, Falcini F. Osteoporosis in juvenile systemic lupus erythematosus: a longitudinal study on the effect of steroids on bone mineral density. Rheumatol Int. 1998;18(2):45–49. doi: 10.1007/s002960050056. [DOI] [PubMed] [Google Scholar]
- 33.Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003 Sep;82(5):299–308. doi: 10.1097/01.md.0000091181.93122.55. [DOI] [PubMed] [Google Scholar]
- 34.Pineau CA, Urowitz MB, Fortin PJ, Ibanez D, Gladman DD. Osteoporosis in systemic lupus erythematosus: factors associated with referral for bone mineral density studies, prevalence of osteoporosis and factors associated with reduced bone density. Lupus. 2004;13(6):436–441. doi: 10.1191/0961203303lu1036oa. [DOI] [PubMed] [Google Scholar]
- 35.Yeap SS, Fauzi AR, Kong NC, et al. A comparison of calcium, calcitriol, and alendronate in corticosteroid-treated premenopausal patients with systemic lupus erythematosus. J Rheumatol. 2008 Dec;35(12):2344–2347. doi: 10.3899/jrheum.080634. [DOI] [PubMed] [Google Scholar]
- 36.Wright TBSJ, Leonard MB, Zemel BS, Burnham JM. Hypovitaminosis D is associated with greater body mass index and disease activity in pediatric systemic lupus erythematosus. J Pediatr. 2009 Aug;155(2):260–265. doi: 10.1016/j.jpeds.2009.02.033. Epub 2009 May 15. [DOI] [PubMed] [Google Scholar]
- 37.Zappitelli M, Duffy CM, Bernard C, Gupta IR. Evaluation of activity, chronicity and tubulointerstitial indices for childhood lupus nephritis. Pediatr Nephrol. 2008 Jan;23(1):83–91. doi: 10.1007/s00467-007-0619-7. [DOI] [PubMed] [Google Scholar]
- 38.Marks SD, Sebire NJ, Pilkington C, Tullus K. Clinicopathological correlations of paediatric lupus nephritis. Pediatr Nephrol. 2007 Jan;22(1):77–83. doi: 10.1007/s00467-006-0296-y. [DOI] [PubMed] [Google Scholar]
- 39.Brunner HI, Silverman ED, To T, Bombardier C, Feldman BM. Risk factors for damage in childhood-onset systemic lupus erythematosus: cumulative disease activity and medication use predict disease damage. Arthritis Rheum. 2002 Feb;46(2):436–444. doi: 10.1002/art.10072. [DOI] [PubMed] [Google Scholar]
- 40.Perfumo F, Martini A. Lupus nephritis in children. Lupus. 2005;14(1):83–88. doi: 10.1191/0961203305lu2065oa. [DOI] [PubMed] [Google Scholar]
- 41.Steinlin MI, Blaser SI, Gilday DL, et al. Neurologic manifestations of pediatric systemic lupus erythematosus. Pediatr Neurol. 1995 Oct;13(3):191–197. doi: 10.1016/0887-8994(95)00110-2. [DOI] [PubMed] [Google Scholar]
- 42.Turkel SB, Miller JH, Reiff A. Case series: neuropsychiatric symptoms with pediatric systemic lupus erythematosus. J Am Acad Child Adolesc Psychiatry. 2001 Apr;40(4):482–485. doi: 10.1097/00004583-200104000-00018. [DOI] [PubMed] [Google Scholar]
- 43.Benseler SM, Silverman ED. Neuropsychiatric involvement in pediatric systemic lupus erythematosus. Lupus. 2007;16(8):564–571. doi: 10.1177/0961203307078971. [DOI] [PubMed] [Google Scholar]
- 44.Olfat MO, Al-Mayouf SM, Muzaffer MA. Pattern of neuropsychiatric manifestations and outcome in juvenile systemic lupus erythematosus. Clin Rheumatol. 2004 Oct;23(5):395–399. doi: 10.1007/s10067-004-0898-3. [DOI] [PubMed] [Google Scholar]
- 45.Sibbitt WL, Jr, Brandt JR, Johnson CR, et al. The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus. J Rheumatol. 2002 Jul;29(7):1536–1542. [PubMed] [Google Scholar]
- 46.Hanly JG, Urowitz MB, Su L, et al. Short-term outcome of neuropsychiatric events in systemic lupus erythematosus upon enrollment into an international inception cohort study. Arthritis Rheum. 2008 May 15;59(5):721–729. doi: 10.1002/art.23566. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Muscal E, Myones BL. The role of autoantibodies in pediatric neuropsychiatric systemic lupus erythematosus. Autoimmun Rev. 2007 Mar;6(4):215–217. doi: 10.1016/j.autrev.2006.08.003. [DOI] [PubMed] [Google Scholar]
- 48.Rivest C, Lew RA, Welsing PM, et al. Association between clinical factors, socioeconomic status, and organ damage in recent onset systemic lupus erythematosus. J Rheumatol. 2000 Mar;27(3):680–684. [PubMed] [Google Scholar]
- 49.Reiff A, Miller J, Shaham B, Bernstein B, Szer IS. Childhood central nervous system lupus; longitudinal assessment using single photon emission computed tomography. J Rheumatol. 1997 Dec;24(12):2461–2465. [PubMed] [Google Scholar]
- 50.Parikh S, Swaiman KF, Kim Y. Neurologic characteristics of childhood lupus erythematosus. Pediatr Neurol. 1995 Oct;13(3):198–201. doi: 10.1016/0887-8994(95)00186-j. [DOI] [PubMed] [Google Scholar]
- 51.Avcin T, Benseler SM, Tyrrell PN, Cucnik S, Silverman ED. A followup study of antiphospholipid antibodies and associated neuropsychiatric manifestations in 137 children with systemic lupus erythematosus. Arthritis Rheum. 2008 Feb 15;59(2):206–213. doi: 10.1002/art.23334. [DOI] [PubMed] [Google Scholar]
- 52.Harel L, Sandborg C, Lee T, von Scheven E. Neuropsychiatric manifestations in pediatric systemic lupus erythematosus and association with antiphospholipid antibodies. J Rheumatol. 2006 Sep;33(9):1873–1877. [PubMed] [Google Scholar]
- 53.Mikdashi JAEJ, Alarcón GS, Crofford L, Fessler BJ, Schanberg L, Brunner H, Gall V, Kalden JR, Lockshin MD, Liang MH, Roberts N, Schneider M for the Ad Hoc Committee on Lupus Response Criteria: Cognition Sub-committee. Proposed response criteria for neurocognitive impairment in systemic lupus erythematosus clinical trials. Lupus. 2007;16:418–425. doi: 10.1177/0961203307079044. [DOI] [PubMed] [Google Scholar]
- 54.Brunner HZF, Levy D, Schanberg L, Anthony K, Ross G, Klein-Gitelman M. Standardizing the Neuropsychological Evaluation of Children with Systemic Lupus Erythematosus. 7th European Lupus Congress, Amsterdam. Lupus. 2008;17(32):467. [Google Scholar]
- 55.Doherty NE, Siegel RJ. Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J. 1985 Dec;110(6):1257–1265. doi: 10.1016/0002-8703(85)90023-7. [DOI] [PubMed] [Google Scholar]
- 56.Miller DJ, Maisch SA, Perez MD, Kearney DL, Feltes TF. Fatal myocardial infarction in an 8-year-old girl with systemic lupus erythematosus, Raynaud's phenomenon, and secondary antiphospholipid antibody syndrome. J Rheumatol. 1995 Apr;22(4):768–773. [PubMed] [Google Scholar]
- 57.Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003 Dec 18;349(25):2407–2415. doi: 10.1056/NEJMoa035611. [DOI] [PubMed] [Google Scholar]
- 58.Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997 Mar 1;145(5):408–415. doi: 10.1093/oxfordjournals.aje.a009122. [DOI] [PubMed] [Google Scholar]
- 59.Al-Abbad AJ, Cabral DA, Sanatani S, et al. Echocardiography and pulmonary function testing in childhood onset systemic lupus erythematosus. Lupus. 2001;10(1):32–37. doi: 10.1191/096120301669980721. [DOI] [PubMed] [Google Scholar]
- 60.Swigris JJ, Fischer A, Gillis J, Meehan RT, Brown KK. Pulmonary and thrombotic manifestations of systemic lupus erythematosus. Chest. 2008 Jan;133(1):271–280. doi: 10.1378/chest.07-0079. [DOI] [PubMed] [Google Scholar]
- 61.Memet B, Ginzler EM. Pulmonary manifestations of systemic lupus erythematosus. Semin Respir Crit Care Med. 2007 Aug;28(4):441–450. doi: 10.1055/s-2007-985665. [DOI] [PubMed] [Google Scholar]
- 62.Murin S, Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med. 1998 Dec;19(4):641–665. doi: 10.1016/s0272-5231(05)70108-8. viii. [DOI] [PubMed] [Google Scholar]
- 63.Ferguson PJ, Weinberger M. Shrinking lung syndrome in a 14-year-old boy with systemic lupus erythematosus. Pediatr Pulmonol. 2006 Feb;41(2):194–197. doi: 10.1002/ppul.20357. [DOI] [PubMed] [Google Scholar]
- 64.Karim MY, Miranda LC, Tench CM, et al. Presentation and prognosis of the shrinking lung syndrome in systemic lupus erythematosus. Semin Arthritis Rheum. 2002 Apr;31(5):289–298. doi: 10.1053/sarh.2002.32555. [DOI] [PubMed] [Google Scholar]
- 65.Samad AS, Lindsley CB. Treatment of pulmonary hemorrhage in childhood systemic lupus erythematosus with mycophenolate mofetil. South Med J. 2003 Jul;96(7):705–707. doi: 10.1097/01.SMJ.0000054424.20202.7D. [DOI] [PubMed] [Google Scholar]
- 66.Byun JY, Ha HK, Yu SY, et al. CT features of systemic lupus erythematosus in patients with acute abdominal pain: emphasis on ischemic bowel disease. Radiology. 1999 Apr;211(1):203–209. doi: 10.1148/radiology.211.1.r99mr17203. [DOI] [PubMed] [Google Scholar]
- 67.Lee CK, Ahn MS, Lee EY, et al. Acute abdominal pain in systemic lupus erythematosus: focus on lupus enteritis (gastrointestinal vasculitis) Ann Rheum Dis. 2002 Jun;61(6):547–550. doi: 10.1136/ard.61.6.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Richer O, Ulinski T, Lemelle I, et al. Abdominal manifestations in childhood-onset systemic lupus erythematosus. Ann Rheum Dis. 2007 Feb;66(2):174–178. doi: 10.1136/ard.2005.050070. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Yu HH, Wang LC, Lee JH, Lee CC, Yang YH, Chiang BL. Lymphopenia is associated with neuropsychiatric manifestations and disease activity in paediatric systemic lupus erythematosus patients. Rheumatology (Oxford) 2007 Sep;46(9):1492–1494. doi: 10.1093/rheumatology/kem182. [DOI] [PubMed] [Google Scholar]
- 70.Martinez-Banos D, Crispin JC, Lazo-Langner A, Sanchez-Guerrero J. Moderate and severe neutropenia in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2006 Aug;45(8):994–998. doi: 10.1093/rheumatology/kel016. [DOI] [PubMed] [Google Scholar]
- 71.Schmugge M, Revel-Vilk S, Hiraki L, Rand ML, Blanchette VS, Silverman ED. Thrombocytopenia and thromboembolism in pediatric systemic lupus erythematosus. J Pediatr. 2003 Nov;143(5):666–669. doi: 10.1067/S0022-3476(03)00389-5. [DOI] [PubMed] [Google Scholar]
- 72.Pamuk GE, Pamuk ON, Baslar Z, et al. Overview of 321 patients with idiopathic thrombocytopenic purpura. Retrospective analysis of the clinical features and response to therapy. Ann Hematol. 2002 Aug;81(8):436–440. doi: 10.1007/s00277-002-0488-x. [DOI] [PubMed] [Google Scholar]
- 73.Altintas A, Ozel A, Okur N, Cil T, Pasa S, Ayyildiz O. Prevalence and clinical significance of elevated antinuclear antibody test in children and adult patients with idiopathic thrombocytopenic purpura. J Thromb Thrombolysis. 2007 Oct;24(2):163–168. doi: 10.1007/s11239-007-0031-y. [DOI] [PubMed] [Google Scholar]
- 74.Brunner HI, Freedman M, Silverman ED. Close relationship between systemic lupus erythematosus and thrombotic thrombocytopenic purpura in childhood. Arthritis Rheum. 1999 Nov;42(11):2346–2355. doi: 10.1002/1529-0131(199911)42:11<2346::AID-ANR13>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
- 75.Wu CY, Su YT, Wang JS, Chiou YH. Childhood hermolytic uremic syndrome associated with systemic lupus erythematosus. Lupus. 2007;16(12):1006–1010. doi: 10.1177/0961203307082385. [DOI] [PubMed] [Google Scholar]
- 76.Musio F, Bohen EM, Yuan CM, Welch PG. Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus. Semin Arthritis Rheum. 1998 Aug;28(1):1–19. doi: 10.1016/s0049-0172(98)80023-1. [DOI] [PubMed] [Google Scholar]
- 77.Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979 Sep;44(3):993–1002. doi: 10.1002/1097-0142(197909)44:3<993::aid-cncr2820440329>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- 78.Wong KF, Hui PK, Chan JK, Chan YW, Ha SY. The acute lupus hemophagocytic syndrome. Ann Intern Med. 1991 Mar 1;114(5):387–390. doi: 10.7326/0003-4819-114-5-387. [DOI] [PubMed] [Google Scholar]
- 79.Oka Y, Kameoka J, Hirabayashi Y, et al. Reversible bone marrow dysplasia in patients with systemic lupus erythematosus. Intern Med. 2008;47(8):737–742. doi: 10.2169/internalmedicine.47.0607. [DOI] [PubMed] [Google Scholar]
- 80.Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis. 2009 Feb;68(2):238–241. doi: 10.1136/ard.2008.093013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Berube C, Mitchell L, Silverman E, et al. The relationship of antiphospholipid antibodies to thromboembolic events in pediatric patients with systemic lupus erythematosus: a cross-sectional study. Pediatr Res. 1998 Sep;44(3):351–356. doi: 10.1203/00006450-199809000-00014. [DOI] [PubMed] [Google Scholar]
- 82.Iwata N, Mori M, Miyamae T, Ito S, Imagawa T, Yokota S. Sjogren's syndrome associated with childhood-onset systemic lupus erythematosus. Nihon Rinsho Meneki Gakkai Kaishi. 2008 Jun;31(3):166–171. doi: 10.2177/jsci.31.166. [DOI] [PubMed] [Google Scholar]
- 83.Ostuni PA, Ianniello A, Sfriso P, Mazzola G, Andretta M, Gambari PF. Juvenile onset of primary Sjogren's syndrome: report of 10 cases. Clin Exp Rheumatol. 1996 Nov–Dec;14(6):689–693. [PubMed] [Google Scholar]
- 84.Stiller M, Golder W, Doring E, Biedermann T. Primary and secondary Sjogren's syndrome in children--a comparative study. Clin Oral Investig. 2000 Sep;4(3):176–182. doi: 10.1007/s007840000070. [DOI] [PubMed] [Google Scholar]
- 85.Chikanza IC, Kuis W, Heijnen CJ. The influence of the hormonal system on pediatric rheumatic diseases. Rheum Dis Clin North Am. 2000 Nov;26(4):911–925. doi: 10.1016/s0889-857x(05)70176-9. [DOI] [PubMed] [Google Scholar]
- 86.Ilowite NT, Samuel P, Ginzler E, Jacobson MS. Dyslipoproteinemia in pediatric systemic lupus erythematosus. Arthritis Rheum. 1988 Jul;31(7):859–863. doi: 10.1002/art.1780310706. [DOI] [PubMed] [Google Scholar]
- 87.Soep JB, Mietus-Snyder M, Malloy MJ, Witztum JL, von Scheven E. Assessment of atherosclerotic risk factors and endothelial function in children and young adults with pediatric-onset systemic lupus erythematosus. Arthritis Rheum. 2004 Jun 15;51(3):451–457. doi: 10.1002/art.20392. [DOI] [PubMed] [Google Scholar]
- 88.Compeyrot-Lacassagne S, Tyrrell PN, Atenafu E, et al. Prevalence and etiology of low bone mineral density in juvenile systemic lupus erythematosus. Arthritis Rheum. 2007 Jun;56(6):1966–1973. doi: 10.1002/art.22691. [DOI] [PubMed] [Google Scholar]
- 89.Hua X, Su J, Svenungsson E, et al. Dyslipidaemia and lipoprotein pattern in systemic lupus erythematosus (SLE) and SLE-related cardiovascular disease. Scand J Rheumatol. 2009 May–Jun;38(3):184–189. doi: 10.1080/03009740802541470. [DOI] [PubMed] [Google Scholar]
- 90.Tyrrell PN, Beyene J, Benseler SM, Sarkissian T, Silverman ED. Predictors of lipid abnormalities in children with new-onset systemic lupus erythematosus. J Rheumatol. 2007 Oct;34(10):2112–2119. [PubMed] [Google Scholar]
- 91.El Magadmi M, Ahmad Y, Turkie W, et al. Hyperinsulinemia, insulin resistance, and circulating oxidized low density lipoprotein in women with systemic lupus erythematosus. J Rheumatol. 2006 Jan;33(1):50–56. [PubMed] [Google Scholar]
- 92.Chung CP, Avalos I, Oeser A, et al. High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis. 2007 Feb;66(2):208–214. doi: 10.1136/ard.2006.054973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Appenzeller S, Pallone AT, Natalin RA, Costallat LT. Prevalence of thyroid dysfunction in systemic lupus erythematosus. J Clin Rheumatol. 2009 Apr;15(3):117–119. doi: 10.1097/RHU.0b013e31819dbe4c. [DOI] [PubMed] [Google Scholar]
- 94.Eberhard BA, Laxer RM, Eddy AA, Silverman ED. Presence of thyroid abnormalities in children with systemic lupus erythematosus. J Pediatr. 1991 Aug;119(2):277–279. doi: 10.1016/s0022-3476(05)80741-3. [DOI] [PubMed] [Google Scholar]
- 95.Athreya BH, Rafferty JH, Sehgal GS, Lahita RG. Adenohypophyseal and sex hormones in pediatric rheumatic diseases. J Rheumatol. 1993 Apr;20(4):725–730. [PubMed] [Google Scholar]
- 96.Ronchezel MV, Len CA, Spinola e Castro A, et al. Thyroid function and serum prolactin levels in patients with juvenile systemic lupus erythematosus. J Pediatr Endocrinol Metab. 2001 Feb;14(2):165–169. doi: 10.1515/jpem.2001.14.2.165. [DOI] [PubMed] [Google Scholar]
- 97.Koller MD, Templ E, Riedl M, et al. Pituitary function in patients with newly diagnosed untreated systemic lupus erythematosus. Ann Rheum Dis. 2004 Dec;63(12):1677–1680. doi: 10.1136/ard.2003.018325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Silva CA, Leal MM, Leone C, et al. Gonadal function in adolescents and young women with juvenile systemic lupus erythematosus. Lupus. 2002;11(7):419–425. doi: 10.1191/0961203302lu219oa. [DOI] [PubMed] [Google Scholar]
- 99.Huong DL, Amoura Z, Benseler SM, et al. Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol. 2002 Dec;29(12):2571–2576. [PubMed] [Google Scholar]
- 100.Silva CA, Hilario MO, Febronio MV, et al. Risk factors for amenorrhea in juvenile systemic lupus erythematosus (JSLE): a Brazilian multicentre coort study. Lupus. 2007;16(7):531–536. doi: 10.1177/0961203307079300. [DOI] [PubMed] [Google Scholar]
- 101.Brunner HI, Bishnoi A, Barron AC, et al. Disease outcomes and ovarian function of childhood-onset systemic lupus erythematosus. Lupus. 2006;15(4):198–206. doi: 10.1191/0961203306lu2291oa. [DOI] [PubMed] [Google Scholar]
- 102.Silva CA, Brunner HI. Gonadal functioning and preservation of reproductive fitness with juvenile systemic lupus erythematosus. Lupus. 2007;16(8):593–599. doi: 10.1177/0961203307077538. [DOI] [PubMed] [Google Scholar]
- 103.Silva CA, Hallak J, Pasqualotto FF, Barba MF, Saito MI, Kiss MH. Gonadal function in male adolescents and young males with juvenile onset systemic lupus erythematosus. J Rheumatol. 2002 Sep;29(9):2000–2005. [PubMed] [Google Scholar]
- 104.Suehiro RM, Borba EF, Bonfa E, et al. Testicular Sertoli cell function in male systemic lupus erythematosus. Rheumatology (Oxford) 2008 Nov;47(11):1692–1697. doi: 10.1093/rheumatology/ken338. [DOI] [PubMed] [Google Scholar]
- 105.Perilloux BC, Shetty AK, Leiva LE, Gedalia A. Antinuclear antibody (ANA) and ANA profile tests in children with autoimmune disorders: a retrospective study. Clin Rheumatol. 2000;19(3):200–203. doi: 10.1007/s100670050156. [DOI] [PubMed] [Google Scholar]
- 106.Fox RI. Sjogren's syndrome. Lancet. 2005 Jul 23–29;366(9482):321–331. doi: 10.1016/S0140-6736(05)66990-5. [DOI] [PubMed] [Google Scholar]
- 107.McGhee JL, Kickingbird LM, Jarvis JN. Clinical utility of antinuclear antibody tests in children. BMC Pediatr. 2004 Jul 9;4:13. doi: 10.1186/1471-2431-4-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Breda L, Nozzi M, De Sanctis S, Chiarelli F. Laboratory Tests in the Diagnosis and Follow-Up of Pediatric Rheumatic Diseases. An Update. Semin Arthritis Rheum. 2009 Feb 24; doi: 10.1016/j.semarthrit.2008.12.001. [DOI] [PubMed] [Google Scholar]
- 109.Esdaile JM, Abrahamowicz M, Joseph L, MacKenzie T, Li Y, Danoff D. Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus. Why some tests fail. Arthritis Rheum. 1996 Mar;39(3):370–378. doi: 10.1002/art.1780390304. [DOI] [PubMed] [Google Scholar]
- 110.Isenberg DA, Collins C. Detection of cross-reactive anti-DNA antibody idiotypes on renal tissue-bound immunoglobulins from lupus patients. J Clin Invest. 1985 Jul;76(1):287–294. doi: 10.1172/JCI111959. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Reichlin M, Broyles TF, Hubscher O, et al. Prevalence of autoantibodies to ribosomal P proteins in juvenile-onset systemic lupus erythematosus compared with the adult disease. Arthritis Rheum. 1999 Jan;42(1):69–75. doi: 10.1002/1529-0131(199901)42:1<69::AID-ANR9>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
- 112.To CH, Petri M. Is antibody clustering predictive of clinical subsets and damage in systemic lupus erythematosus? Arthritis Rheum. 2005 Dec;52(12):4003–4010. doi: 10.1002/art.21414. [DOI] [PubMed] [Google Scholar]
- 113.Jurencak R, Fritzler M, Tyrrell P, Hiraki L, Benseler S, Silverman E. Autoantibodies in pediatric systemic lupus erythematosus: ethnic grouping, cluster analysis, and clinical correlations. J Rheumatol. 2009 Feb;36(2):416–421. doi: 10.3899/jrheum.080588. [DOI] [PubMed] [Google Scholar]
- 114.Campos LM, Kiss MH, Scheinberg MA, Mangueira CL, Silva CA. Antinucleosome antibodies in patients with juvenile systemic lupus erythematosus. Lupus. 2006;15(8):496–500. doi: 10.1191/0961203306lu2317oa. [DOI] [PubMed] [Google Scholar]
- 115.Tikly M, Gould T, Wadee AA, van der Westhuizenx E, Mokgethwa BB. Clinical and serological correlates of antinucleosome antibodies in South Africans with systemic lupus erythematosus. Clin Rheumatol. 2007 Dec;26(12):2121–2125. doi: 10.1007/s10067-007-0637-7. [DOI] [PubMed] [Google Scholar]
- 116.Lettre G, Rioux JD. Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet. 2008 Oct 15;17(R2):R116–R121. doi: 10.1093/hmg/ddn246. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Pickering MC, Walport MJ. Links between complement abnormalities and systemic lupus erythematosus. Rheumatology (Oxford) 2000 Feb;39(2):133–141. doi: 10.1093/rheumatology/39.2.133. [DOI] [PubMed] [Google Scholar]
- 118.Kallel-Sellami M, Baili-Klila L, Zerzeri Y, et al. Hereditary complement deficiency and lupus: report of four Tunisian cases. Ann N Y Acad Sci. 2007 Jun;1108:197–202. doi: 10.1196/annals.1422.022. [DOI] [PubMed] [Google Scholar]
- 119.Yang Y, Lhotta K, Chung EK, Eder P, Neumair F, Yu CY. Complete complement components C4A and C4B deficiencies in human kidney diseases and systemic lupus erythematosus. J Immunol. 2004 Aug 15;173(4):2803–2814. doi: 10.4049/jimmunol.173.4.2803. [DOI] [PubMed] [Google Scholar]
- 120.Reveille JD, Schrohenloher RE, Actonx RT, Barger BO. DNA analysis of HLA-DR and DQ genes in American blacks with systemic lupus erythematosus. Arthritis Rheum. 1989 Oct;32(10):1243–1251. doi: 10.1002/anr.1780321009. [DOI] [PubMed] [Google Scholar]
- 121.Barron KS, Silverman ED, Gonzales J, Reveille JD. Clinical, serologic, and immunogenetic studies in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 1993 Mar;36(3):348–354. doi: 10.1002/art.1780360310. [DOI] [PubMed] [Google Scholar]
- 122.Baca V, Catalan T, Villasis-Keever M, Ramon G, Morales AM, Rodriguez-Leyva F. Effect of low-dose cyclosporine A in the treatment of refractory proteinuria in childhood-onset lupus nephritis. Lupus. 2006;15(8):490–495. doi: 10.1191/0961203306lu2312oa. [DOI] [PubMed] [Google Scholar]
- 123.Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004 Sep;75(3):504–507. doi: 10.1086/423790. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.Liao CH, Yao TC, Chung HT, See LC, Kuo ML, Huang JL. Polymorphisms in the promoter region of RANTES and the regulatory region of monocyte chemoattractant protein-1 among Chinese children with systemic lupus erythematosus. J Rheumatol. 2004 Oct;31(10):2062–2067. [PubMed] [Google Scholar]
- 125.Jacob CO, Reiff A, Armstrong DL, et al. Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platformx. Arthritis Rheum. 2007 Dec;56(12):4164–4173. doi: 10.1002/art.23060. [DOI] [PubMed] [Google Scholar]
- 126.Velazquez-Cruz R, Orozco L, Espinosa-Rosales F, et al. Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus. Eur J Hum Genet. 2007 Mar;15(3):336–341. doi: 10.1038/sj.ejhg.5201767. [DOI] [PubMed] [Google Scholar]
- 127.Brunner HI, Klein-Gitelman MS, Ying J, Tucker LB, Silverman ED. Corticosteroid use in childhood-onset systemic lupus erythematosus-practice patterns at four pediatric rheumatology centers. Clin Exp Rheumatol. 2009 Jan–Feb;27(1):155–162. [PubMed] [Google Scholar]
- 128.Kumar S, Benseler SM, Kirby-Allen M, Silverman ED. B-cell depletion for autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric systemic lupus erythematosus. Pediatrics. 2009 Jan;123(1):e159–e163. doi: 10.1542/peds.2008-2361. [DOI] [PubMed] [Google Scholar]
- 129.Baca V, Lavalle C, Garcia R, et al. Favorable response to intravenous methylprednisolone and cyclophosphamide in children with severe neuropsychiatric lupus. J Rheumatol. 1999 Feb;26(2):432–439. [PubMed] [Google Scholar]
- 130.Levy DM, Massicotte MP, Harvey E, Hebert D, Silverman ED. Thromboembolism in paediatric lupus patients. Lupus. 2003;12(10):741–746. doi: 10.1191/0961203303lu458oa. [DOI] [PubMed] [Google Scholar]
- 131.Harrison MJ, Ravdin LD, Lockshin MD. Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus. Arthritis Rheum. 2006 Aug;54(8):2515–2522. doi: 10.1002/art.22030. [DOI] [PubMed] [Google Scholar]
- 132.Bertsias G, Boumpas DT. Update on the management of lupus nephritis: let the treatment fit the patient. Nat Clin Pract Rheumatol. 2008 Sep;4(9):464–472. doi: 10.1038/ncprheum0896. [DOI] [PubMed] [Google Scholar]
- 133.Niaudet P. Treatment of lupus nephritis in children. Pediatr Nephrol. 2000 Feb;14(2):158–166. doi: 10.1007/s004670050034. [DOI] [PubMed] [Google Scholar]
- 134.Barbano G, Gusmano R, Damasio B, et al. Childhood-onset lupus nephritis: a single-center experience of pulse intravenous cyclophosphamide therapy. J Nephrol. 2002 Mar–Apr;15(2):123–129. [PubMed] [Google Scholar]
- 135.Lehman TJ, Onel K. Intermittent intravenous cyclophosphamide arrests progression of the renal chronicity index in childhood systemic lupus erythematosus. J Pediatr. 2000 Feb;136(2):243–247. doi: 10.1016/s0022-3476(00)70109-0. [DOI] [PubMed] [Google Scholar]
- 136.Lehman TJ, Edelheit BS, Onel KB. Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis. Ann Rheum Dis. 2004 Mar;63(3):321–323. doi: 10.1136/ard.2003.008342. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.Falcini F, Capannini S, Martini G, et al. Mycophenolate mofetil for the treatment of juvenile onset SLE: a multicenter study. Lupus. 2009 Feb;18(2):139–143. doi: 10.1177/0961203308094999. [DOI] [PubMed] [Google Scholar]
- 138.Hagelberg S, Lee Y, Bargman J, et al. Longterm followup of childhood lupus nephritis. J Rheumatol. 2002 Dec;29(12):2635–2642. [PubMed] [Google Scholar]
- 139.Lionaki S, Kapitsinou PP, Iniotaki A, Kostakis A, Moutsopoulos HM, Boletis JN. Kidney transplantation in lupus patients: a case-control study from a single centre. Lupus. 2008 Jul;17(7):670–675. doi: 10.1177/0961203308089430. [DOI] [PubMed] [Google Scholar]
- 140.Cochat P, Fargue S, Mestrallet G, et al. Disease recurrence in paediatric renal transplantation. Pediatr Nephrol. 2009 Feb 27; doi: 10.1007/s00467-009-1137-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.Ghafari A, Etemadi J, Ardalan MR. Renal transplantation in patients with lupus nephritis: a single-center experience. Transplant Proc. 2008 Jan–Feb;40(1):143–144. doi: 10.1016/j.transproceed.2007.12.013. [DOI] [PubMed] [Google Scholar]
- 142.Moroni G, Tantardini F, Gallelli B, et al. The long-term prognosis of renal transplantation in patients with lupus nephritis. Am J Kidney Dis. 2005 May;45(5):903–911. doi: 10.1053/j.ajkd.2005.01.038. [DOI] [PubMed] [Google Scholar]
- 143.Drenkard C, Villa AR, Garcia-Padilla C, Perez-Vazquez ME, Alarcon-Segovia D. Remission of systematic lupus erythematosus. Medicine (Baltimore) 1996 Mar;75(2):88–98. doi: 10.1097/00005792-199603000-00005. [DOI] [PubMed] [Google Scholar]
- 144.Urowitz MB, Feletar M, Bruce IN, Ibanez D, von Scheven E. Prolonged remission in systemic lupus erythematosus. J Rheumatol. 2005 Aug;32(8):1467–1472. [PubMed] [Google Scholar]
- 145.Cook CD, Wedgwood RJ, Craig JM, Hartmann JR, Janeway CA. Systemic lupus erythematosus. Description of 37 cases in children and a discussion of endocrine therapy in 32 of the cases. Pediatrics. 1960 Oct;26:570–585. [PubMed] [Google Scholar]
- 146.Glidden RS, Mantzouranis EC, Borel Y. Systemic lupus erythematosus in childhood: clinical manifestations and improved survival in fifty-five patients. Clin Immunol Immunopathol. 1983 Nov;29(2):196–210. doi: 10.1016/0090-1229(83)90024-7. [DOI] [PubMed] [Google Scholar]
- 147.Gonzalez B, Hernandez P, Olguin H, et al. Changes in the survival of patients with systemic lupus erythematosus in childhood: 30 years experience in Chile. Lupus. 2005;14(11):918–923. doi: 10.1191/0961203303lu2183xx. [DOI] [PubMed] [Google Scholar]
- 148.Urowitz MB, Gladman DD, Tom BD, Ibanez D, Farewell VT. Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol. 2008 Nov;35(11):2152–2158. doi: 10.3899/jrheum.080214. [DOI] [PubMed] [Google Scholar]
- 149.Chambers SA, Allen E, Rahman A, Isenberg D. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford) 2009 Jun;48(6):673–675. doi: 10.1093/rheumatology/kep062. [DOI] [PubMed] [Google Scholar]
- 150.Doria A, Iaccarino L, Ghirardello A, et al. Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med. 2006 Aug;119(8):700–706. doi: 10.1016/j.amjmed.2005.11.034. [DOI] [PubMed] [Google Scholar]
- 151.Moss KE, Ioannou Y, Sultan SM, Haq I, Isenberg DA. Outcome of a cohort of 300 patients with systemic lupus erythematosus attending a dedicated clinic for over two decades. Ann Rheum Dis. 2002 May;61(5):409–413. doi: 10.1136/ard.61.5.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1999 May;78(3):167–175. doi: 10.1097/00005792-199905000-00003. [DOI] [PubMed] [Google Scholar]
- 153.Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006 Aug;54(8):2550–2557. doi: 10.1002/art.21955. [DOI] [PubMed] [Google Scholar]
- 154.Cervera R, Abarca-Costalago M, Abramovicz D, et al. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the "Euro-Lupus Project". Autoimmun Rev. 2006 Mar;5(3):180–186. doi: 10.1016/j.autrev.2005.06.004. [DOI] [PubMed] [Google Scholar]
- 155.Bandeira M, Buratti S, Bartoli M, et al. Relationship between damage accrual, disease flares and cumulative drug therapies in juvenile-onset systemic lupus erythematosus. Lupus. 2006;15(8):515–520. doi: 10.1191/0961203306lu2316oa. [DOI] [PubMed] [Google Scholar]
- 156.Fernandez M, Alarcon GS, Apte M, Andrade RM, Vila LM, Reveille JD. Systemic lupus erythematosus in a multiethnic US cohort: XLIII. The significance of thrombocytopenia as a prognostic factor. Arthritis Rheum. 2007 Feb;56(2):614–621. doi: 10.1002/art.22376. [DOI] [PubMed] [Google Scholar]
- 157.Mok CC, To CH, Ho LY, Yu KL. Incidence and mortality of systemic lupus erythematosus in a southern Chinese population, 2000–2006. J Rheumatol. 2008 Oct;35(10):1978–1982. [PubMed] [Google Scholar]
- 158.Koneru S, Shishov M, Ware A, et al. Effectively measuring adherence to medications for systemic lupus erythematosus in a clinical setting. Arthritis Rheum. 2007 Aug 15;57(6):1000–1006. doi: 10.1002/art.22898. [DOI] [PubMed] [Google Scholar]
- 159.Ting VKD, Nelson S, Huggins J, Eaton J, Rammel J, Drotar D, Brunner HI. Use of Cellular Text Messaging to Improve Visit Adherence in Adolescents with Childhood-onset Systemic Lupus Erythematosus (cSLE) ACR. 2009 [Google Scholar]
- 160.Al Dhanhani AM, Gignac MA, Su J, Fortin PR. Work disability in systemic lupus erythematosus. Arthritis Rheum. 2009 Mar 15;61(3):378–385. doi: 10.1002/art.24347. [DOI] [PubMed] [Google Scholar]
- 161.Reiff A. Childhood quality of life in the changing landscape of pediatric rheumatology. J Pediatr (Rio J) 2008 Jul–Aug;84(4):285–288. doi: 10.2223/JPED.1808. [DOI] [PubMed] [Google Scholar]
- 162.Becker-Merok A, Nossent HC. Damage accumulation in systemic lupus erythematosus and its relation to disease activity and mortality. J Rheumatol. 2006 Aug;33(8):1570–1577. [PubMed] [Google Scholar]
- 163.Gutierrez-Suarez R, Ruperto N, Gastaldi R, et al. A proposal for a pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index based on the analysis of 1,015 patients with juvenile-onset systemic lupus erythematosus. Arthritis Rheum. 2006 Sep;54(9):2989–2996. doi: 10.1002/art.22048. [DOI] [PubMed] [Google Scholar]
- 164.Brunner HI, Sherrard TM, Klein-Gitelman MS. Cost of treatment of childhood-onset systemic lupus erythematosus. Arthritis Rheum. 2006 Apr 15;55(2):184–188. doi: 10.1002/art.21845. [DOI] [PubMed] [Google Scholar]
- 165.Lau CSMA. The socioeconomic burden of SLE. Nat Rev Rheumatol.2009. 2009 Jul;5(7):400–404. doi: 10.1038/nrrheum.2009.106. [DOI] [PubMed] [Google Scholar]
- 166.Sutcliffe N, Clarke AE, Taylor R, Frost C, Isenberg DA. Total costs and predictors of costs in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2001 Jan;40(1):37–47. doi: 10.1093/rheumatology/40.1.37. [DOI] [PubMed] [Google Scholar]