Abstract
Paediatric-onset systemic lupus erythematosus (SLE) is usually more severe than its adult counterpart. In particular, there is a higher incidence of renal and central nervous system involvement. Specific measures to assess disease activity and damage have been implemented. The disease is very rare before the fifth birthday and therefore the onset of an SLE picture in the first years of life should lead to the suspicion of the presence of one of the rare monogenic diseases that causes SLE or of one of those congenital diseases that has been showed to be closely associated with the SLE.
Introduction
Paediatric-onset systemic lupus erythematosus (pSLE) accounts for about 10–20% of all patients with SLE. Disease onset most frequently occurs between the ages of 12 and 16 years, is uncommon before the age of 10 years and is very rare before 5 years. pSLE has an incidence of 0.36–0.9 per 100,000 children per year and a prevalence, which varies considerably according to ethnicity, of 3.3–24 per 100,000 children . Female preponderance is less pronounced in pSLE with respect to adult-onset SLE (aSLE), especially in patients diagnosed before puberty . Unlike other rheumatic diseases such as juvenile idiopathic arthritis or juvenile dermatomyositis, which considerably differs from their counterparts in the adults, pSLE is substantially the same disease as in adults. The American College of Rheumatology (ACR) classification criteria for SLE , indeed, are equally accurate when applied to paediatric patients . Despite the similarities of SLE features across age groups, a substantial difference in the initial symptoms and severity of pSLE and aSLE has however been reported . SLE that begins in childhood is more abrupt in onset with higher rates of organ involvement, more aggressive clinical course and more-rapid damage accrual than aSLE . Whether these differences are due to variation in the biology or genetics of pSLE and aSLE has not yet been fully elucidated. The specific issues that are addressed in this chapter concern the differences between pSLE and aSLE, as well as their impact in everyday clinical practice. Elucidating differences with respect to outcome between pSLE and aSLE may aid in developing tailored treatments based on age at disease onset. Furthermore, genetic susceptibility to SLE and the role of genes in conditioning clinical phenotype are reviewed based on the available scientific evidence.
Is paediatric-onset lupus different from adult lupus?
Differences in disease features
Clinical manifestations and their frequencies in children and adults with SLE are reported in Table 1 . Although the principal signs and symptoms of aSLE and pSLE are identical, children experience a higher frequency of renal, neurologic and haematologic involvement than their adult counterparts . Renal involvement, as shown by abnormal urinalysis and/or renal function, occurs more frequently in paediatric patients, being present in 67–82% of children compared with 33–53% of adults with SLE . Unlike adults, lupus nephritis (LN) is often a presenting feature of paediatric SLE , and in 90% of the patients renal disease occurs within 2 years from disease onset . Distribution of LN histological classes is similar between pSLE and aSLE, with diffuse proliferative LN (class IV), carrying the worst renal prognosis, occurring in 40–60%, focal proliferative LN (class III) in 10–20% and membranous LN (class V) in 3–28% of pSLE patients with renal disease . As in aSLE, histological diagnosis guides treatment and aids in determining overall prognosis. So far, there is no evidence to suggest that the diagnosis, management and monitoring of LN should differ in children vs. adults ; it should be noted, however, that no medication has so far received Food and Drug Administration approval for the treatment of juvenile LN. Currently, the off-label use of drugs that are prescribed in oncology and transplant medicine or that have been found effective in aSLE is standard practice, which likely negatively affects patient safety and drug effectiveness as optimal dosing for pSLE is not well established . Recently, consensus has been reached regarding standardised measures of response to therapy in pSLE , as well as renal response definitions and other outcomes to measure safety and effectiveness of LN treatment plans . These instruments, together with the availability of large international paediatric rheumatology networks, should, in the future, facilitate the implementation of randomised controlled clinical trials devoted to paediatric SLE.
| Clinical features | Paediatric-onset SLE | Adult-onset SLE |
|---|---|---|
| Fever | 20–67% | 43–55% |
| Lymphadenopathy | 6–36% | 0–1% |
| Malar rash | 22–79% | 35–59% |
| Discoid lupus | 0–19% | 3–29% |
| Oral ulcers | 9–49% | 13–40% |
| Photosensitivity | 23–53% | 20–57% |
| Arthritis | 22–88% | 67–94% |
| Nephropathy | 67–82% | 33–53% |
| Pericarditis | 16–26% | 13–33% |
| Pleuritis | 6–48% | 6–33% |
| Neuropsychiatric disease | 15–95% | 33–60% |
| Leucopenia | 46–64% | 41–57% |
| Thrombocytopaenia | 25–37% | 6–25% |
| Hamolytic anaemia | 10–76% | 3–13% |
Likewise, regarding renal disease, Tucker et al., in a longitudinal multi-ethnic study comparing 40 adolescents with SLE with 72 aSLE patients, found that neurological involvement was significantly more common in the adolescent-onset group (38.7% vs. 12.5%; p = 0.009) . Movement disorders and chorea, which are often associated with anti-phospholipid antibodies, are more common in children than in adults , as well as seizures, intracranial hypertension and transient ischaemic attack, as found in the Grupo Latinoamericano de Estudio del Lupus (GLADEL) cohort . Conversely, cranial nerve abnormalities are more frequently encountered in aSLE than in pSLE . In contrast to overt neurologic disease, little is known about sub-clinical neurocognitive dysfunction in pSLE, as age-appropriate standard neuropsychological batteries for pSLE have become available only recently . The finding of a neurocognitive impairment in 46.7–59% of pSLE patients without previous neuropsychiatric involvement or cognitive complaints underscores the need for routine neurocognitive assessment in children with SLE. The recognition of early warning signs of cognitive decline and early educational interventions and psychological support is crucial in childhood as it might have substantial impact on learning and academic and vocational success .
Due to derangement of normal developmental and structural milestones, SLE-related immune and vascular neuropathophysiological mechanisms may have different effects on the developing brain of children compared to the mature brain of adults with SLE. Advances in imaging technologies make it possible to map brain function. Using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI), differences in brain activation patterns, which are related to distinct cognitive deficits, have been demonstrated in a study involving 22 children with pSLE . The authors found that compensatory mechanisms, relying on neuronal plasticity, are elicited to maintain cognitive performance, thus underscoring the potential of this technique to elucidate the impact of the disease on the developing brains of children.
Besides clinical features, different serological patterns have been reported between pSLE and aSLE. Tucker et al. found a higher prevalence of anti-double-stranded DNA (anti-dsDNA) antibodies in children as compared to adults with SLE (85% vs. 54%) . Immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin antibody, antihistone and antiribosomal P antibodies were also more frequently found in pSLE . The disease association of the antibody clustering in paediatric SLE may be different from that observed in aSLE. For instance, the significant association of anti-dsDNA antibodies with renal involvement (odds ratio (OR) = 9.00 (95% CI 2.23–36.33), p ≤ 0.001)) reported in children with pSLE was not confirmed in a control group of 194 aSLE patients, nor was the protective value of antiribosomal P antibodies (in the absence of anti-dsDNA antibodies) on renal disease .
Differences in disease activity
Patients with pSLE showed a significantly higher disease activity score, as measured by the SLE Disease Activity Index, at presentation (16.8 ± 10.1) than did the adults with SLE (9.3 ± 7.6, p < 0.0001), as reported by Brunner et al. in a study comparing Canadian inception cohorts of children ( N = 67) and adults ( N = 131) from the same ethnic and environmental backgrounds, using standardised disease measures . Most of the tools developed to assess disease activity in adult SLE have been validated for use in pSLE over the last decade . The most pronounced differences in disease activity between aSLE and paediatric SLE pertain to renal or neurologic organ systems . Increased SLE activity is likely to result in a greater requirement of aggressive treatments to control the disease, as demonstrated when comparing patients’ therapies in the above-mentioned Canadian cohorts; children with SLE, in fact, were more often prescribed oral corticosteroids than adults (97% vs. 70%) and were treated with intravenous methylprednisolone almost three times more often than adults . Moderate-to-high dose corticosteroid was required by 77% of patients with pSLE compared with 16% of adult-onset patients. Of note, after a mean disease duration of 16.5 years, 68% of patients with childhood-onset SLE were still on oral steroids vs. 43% in the aSLE subgroup ; the former patients were also more likely to report prior and/or current use of mycophenolate mofetil and intravenous (IV) cyclophosphamide . Despite the more frequent use of corticosteroids and immunosuppressive agents, a significantly higher percentage of children with SLE have continued disease activity during the course of the disease when compared to adults . These results suggest that therapeutic regimens tested mostly in adults may not be sufficient to achieve comparable control of overall disease activity in patients with childhood-onset SLE. Furthermore, cumulative disease activity over time has been shown to be a highly significant predictor of disease damage in both children and adults with SLE .
Difference in damage accrual
Overall, most SLE-outcome studies suggest that long-term remission is uncommon and, thus, that children with SLE are prone to suffer more damage due to a longer exposition to higher disease activity and treatment-associated adverse effects than their adult counterparts . Indeed, children with pSLE showed significantly higher mean Systemic Lupus International Collaborating Clinics/American College of Rheumatism (SLICC/ACR) damage index scores (SDIs) than adults with SLE (1.7 vs. 0.76; p = 0.008) , as reported by Brunner in the study comparing Canadian inception cohorts with similar backgrounds. Compared with adults, patients with pSLE had significantly more steroid-associated damage, including cataracts (42% vs. 12%; p = 0.0001) and avascular necrosis (21% vs. 5%; p = 0.0003), a potentially debilitating complication of SLE . Age at the time of initial corticosteroid administration was an independent risk factor for osteonecrosis, as recently demonstrated by Nakamura et al. , who found that the rate of corticosteroid-associated osteonecrosis was significantly lower in paediatric patients (6%) than in patients aged 15–20 years (49%) or adult patients (41%) ( p = 0.0001), probably due to their abundant vascularity with growth plates and red marrow. With the increase of disease duration, children with SLE experienced a significantly higher risk of developing renal damage compared to their adult counterparts (45.2% vs. 17.4%; p = 0.023) ( Table 2 ). In line with these results, subjects with pSLE were more likely to have been on dialysis (nearly 20% vs. 6% of the aSLE patients) or have had renal transplantation (nearly 12% vs. 4% of adults with SLE), as concluded by a long-term study conducted on 885 SLE patients, including 90 children . In the same outcome study, pSLE was found to be an independent risk factor for myocardial infarction (OR = 6.8, 95% confidence interval (CI) 2.3–20.02; p < 0.001), confirming that cardiovascular disease is emerging as a significant cause of early morbidity and mortality in patients with pSLE. Of note, previous studies have reported accelerated carotid intimal thickening , and abnormal myocardial perfusion scans , both markers of atherosclerosis, in children and adolescents with SLE. Overall, these results suggest that a preventative focus is especially important for children and adolescents with SLE who face a lifelong burden of considerably increased cardiovascular risk due to the disease itself or its treatment . As there is a high degree of morbidity in pSLE compared with aSLE , a careful monitoring of damage accrual is of paramount importance. Although the SDI has proven suitable to assess damage in patients with pSLE, it does not capture some forms of damage that are unique to children and adolescents such as growth failure and delayed puberty . Furthermore, SDI covers only irreversible damage and does not take into account the ability of children to recover and regenerate from damage to a greater extent than adults. A modified version of the SDI for use in pSLE was therefore developed through evidence-based scrutiny of potential sources of damage in 1015 patients . Growth failure and delayed puberty were recorded in 15.3% and 11.3% of patients, respectively, and were included as additional organ systems/domains to the original SDI . The negative effect of glucocorticoids on linear growth prior to the closure of growth plates, together with the modification of body image induced by treatment, may represent a major psychological burden especially in adolescents building their self-esteem and may affect treatment compliance. Although delayed puberty is a temporary phenomenon, it may have irreversible consequences due to its interference with physiological events such as the growth spurt or bone mass accretion (which are both already potentially compromised by steroid treatment), potentially leading to final short stature and premature osteoporosis.
| SDI domain | LB Tucker et al . | Brunner HI et al [ ]. | Hersh AO et al [ ]. | |||
|---|---|---|---|---|---|---|
| p-SLE (N=31) | a-SLE (N=48) | p-SLE (N=66) | a-SLE (N=131) | p-SLE(N=90) | a-SLE (N=795) | |
| Mean (SD) total disease duration (years) | 6.8 (2.7) | 5.6 (3.3) | 3.2 (2) | 3.5 (2.6) | 16.5 (8.5) | 13.4 (8.5) |
| Ocular | 9.7% | 4.3% | 42.4% | 13.0% ( p < 0.0001) | ||
| Neuropsychiatric | 29.0% | 19.6% | 12.1% | 9.9% | ||
| Renal | 45.2% | 17.4% ( p = 0.023) | 9.1% | 6.1% | 56.2% | 37.1% ( p < 0.001) |
| Pulmonary | 3.2% | 6.5% | 3.0% | 2.3% | 23.6% | 43.3% ( p < 0.001) |
| Cardiovascular | 6.5% | 4.3% | 1.5% | 4.6% | 7.9% | 4.5% |
| Peripheral vascular | 0.0% | 8.7% | 3.0% | 1.5% | ||
| Gastrointestinal | 3.2% | 10.9% | 3.0% | 2.3% | ||
| Musculoskeletal | 19.4% | 15.2% | 24.2% | 9.9% ( p = 0.007) | ||
| Skin | 9.7% | 15.2% | 7.6% | 6.9% | ||
| Gonadal | 12.9% | 10.9% | 0.0% | 1.5% | ||
| Diabetes | 3.2% | 8.7% | 3.0% | 4.6% | ||
| Malignancy | 3.2% | 0.0% | 0.0% | 3.8% | ||
Not surprisingly, patients with pSLE have lower health-related quality-of-life scores than healthy individuals . Unlike in adults, patients with pSLE have to face the consequences of a chronic disease that potentially interferes with the development and consolidation of self-identity and self-esteem, the ability to establish relationships with peers, the acquisition of independence and the development of vocations. A study that provides information about the socioeconomic outcome of patients with pSLE in adult life showed a low rate of high school and university/college completion, with half of the patients working and 11% receiving disability benefits .
Elucidating differences with respect to outcome between pSLE and aSLE may aid in developing tailor-made treatment strategies based on age at disease onset. Furthermore, a good transition programme from paediatric to adult medicine is very important; transfer of adolescents to a dedicated rheumatologist with specific knowledge of the characteristics of pSLE and the unique needs of these patients is essential to achieving good long-term outcomes.
Is paediatric-onset lupus different from adult lupus?
Differences in disease features
Clinical manifestations and their frequencies in children and adults with SLE are reported in Table 1 . Although the principal signs and symptoms of aSLE and pSLE are identical, children experience a higher frequency of renal, neurologic and haematologic involvement than their adult counterparts . Renal involvement, as shown by abnormal urinalysis and/or renal function, occurs more frequently in paediatric patients, being present in 67–82% of children compared with 33–53% of adults with SLE . Unlike adults, lupus nephritis (LN) is often a presenting feature of paediatric SLE , and in 90% of the patients renal disease occurs within 2 years from disease onset . Distribution of LN histological classes is similar between pSLE and aSLE, with diffuse proliferative LN (class IV), carrying the worst renal prognosis, occurring in 40–60%, focal proliferative LN (class III) in 10–20% and membranous LN (class V) in 3–28% of pSLE patients with renal disease . As in aSLE, histological diagnosis guides treatment and aids in determining overall prognosis. So far, there is no evidence to suggest that the diagnosis, management and monitoring of LN should differ in children vs. adults ; it should be noted, however, that no medication has so far received Food and Drug Administration approval for the treatment of juvenile LN. Currently, the off-label use of drugs that are prescribed in oncology and transplant medicine or that have been found effective in aSLE is standard practice, which likely negatively affects patient safety and drug effectiveness as optimal dosing for pSLE is not well established . Recently, consensus has been reached regarding standardised measures of response to therapy in pSLE , as well as renal response definitions and other outcomes to measure safety and effectiveness of LN treatment plans . These instruments, together with the availability of large international paediatric rheumatology networks, should, in the future, facilitate the implementation of randomised controlled clinical trials devoted to paediatric SLE.
| Clinical features | Paediatric-onset SLE | Adult-onset SLE |
|---|---|---|
| Fever | 20–67% | 43–55% |
| Lymphadenopathy | 6–36% | 0–1% |
| Malar rash | 22–79% | 35–59% |
| Discoid lupus | 0–19% | 3–29% |
| Oral ulcers | 9–49% | 13–40% |
| Photosensitivity | 23–53% | 20–57% |
| Arthritis | 22–88% | 67–94% |
| Nephropathy | 67–82% | 33–53% |
| Pericarditis | 16–26% | 13–33% |
| Pleuritis | 6–48% | 6–33% |
| Neuropsychiatric disease | 15–95% | 33–60% |
| Leucopenia | 46–64% | 41–57% |
| Thrombocytopaenia | 25–37% | 6–25% |
| Hamolytic anaemia | 10–76% | 3–13% |
Likewise, regarding renal disease, Tucker et al., in a longitudinal multi-ethnic study comparing 40 adolescents with SLE with 72 aSLE patients, found that neurological involvement was significantly more common in the adolescent-onset group (38.7% vs. 12.5%; p = 0.009) . Movement disorders and chorea, which are often associated with anti-phospholipid antibodies, are more common in children than in adults , as well as seizures, intracranial hypertension and transient ischaemic attack, as found in the Grupo Latinoamericano de Estudio del Lupus (GLADEL) cohort . Conversely, cranial nerve abnormalities are more frequently encountered in aSLE than in pSLE . In contrast to overt neurologic disease, little is known about sub-clinical neurocognitive dysfunction in pSLE, as age-appropriate standard neuropsychological batteries for pSLE have become available only recently . The finding of a neurocognitive impairment in 46.7–59% of pSLE patients without previous neuropsychiatric involvement or cognitive complaints underscores the need for routine neurocognitive assessment in children with SLE. The recognition of early warning signs of cognitive decline and early educational interventions and psychological support is crucial in childhood as it might have substantial impact on learning and academic and vocational success .
Due to derangement of normal developmental and structural milestones, SLE-related immune and vascular neuropathophysiological mechanisms may have different effects on the developing brain of children compared to the mature brain of adults with SLE. Advances in imaging technologies make it possible to map brain function. Using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI), differences in brain activation patterns, which are related to distinct cognitive deficits, have been demonstrated in a study involving 22 children with pSLE . The authors found that compensatory mechanisms, relying on neuronal plasticity, are elicited to maintain cognitive performance, thus underscoring the potential of this technique to elucidate the impact of the disease on the developing brains of children.
Besides clinical features, different serological patterns have been reported between pSLE and aSLE. Tucker et al. found a higher prevalence of anti-double-stranded DNA (anti-dsDNA) antibodies in children as compared to adults with SLE (85% vs. 54%) . Immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin antibody, antihistone and antiribosomal P antibodies were also more frequently found in pSLE . The disease association of the antibody clustering in paediatric SLE may be different from that observed in aSLE. For instance, the significant association of anti-dsDNA antibodies with renal involvement (odds ratio (OR) = 9.00 (95% CI 2.23–36.33), p ≤ 0.001)) reported in children with pSLE was not confirmed in a control group of 194 aSLE patients, nor was the protective value of antiribosomal P antibodies (in the absence of anti-dsDNA antibodies) on renal disease .
Differences in disease activity
Patients with pSLE showed a significantly higher disease activity score, as measured by the SLE Disease Activity Index, at presentation (16.8 ± 10.1) than did the adults with SLE (9.3 ± 7.6, p < 0.0001), as reported by Brunner et al. in a study comparing Canadian inception cohorts of children ( N = 67) and adults ( N = 131) from the same ethnic and environmental backgrounds, using standardised disease measures . Most of the tools developed to assess disease activity in adult SLE have been validated for use in pSLE over the last decade . The most pronounced differences in disease activity between aSLE and paediatric SLE pertain to renal or neurologic organ systems . Increased SLE activity is likely to result in a greater requirement of aggressive treatments to control the disease, as demonstrated when comparing patients’ therapies in the above-mentioned Canadian cohorts; children with SLE, in fact, were more often prescribed oral corticosteroids than adults (97% vs. 70%) and were treated with intravenous methylprednisolone almost three times more often than adults . Moderate-to-high dose corticosteroid was required by 77% of patients with pSLE compared with 16% of adult-onset patients. Of note, after a mean disease duration of 16.5 years, 68% of patients with childhood-onset SLE were still on oral steroids vs. 43% in the aSLE subgroup ; the former patients were also more likely to report prior and/or current use of mycophenolate mofetil and intravenous (IV) cyclophosphamide . Despite the more frequent use of corticosteroids and immunosuppressive agents, a significantly higher percentage of children with SLE have continued disease activity during the course of the disease when compared to adults . These results suggest that therapeutic regimens tested mostly in adults may not be sufficient to achieve comparable control of overall disease activity in patients with childhood-onset SLE. Furthermore, cumulative disease activity over time has been shown to be a highly significant predictor of disease damage in both children and adults with SLE .
Difference in damage accrual
Overall, most SLE-outcome studies suggest that long-term remission is uncommon and, thus, that children with SLE are prone to suffer more damage due to a longer exposition to higher disease activity and treatment-associated adverse effects than their adult counterparts . Indeed, children with pSLE showed significantly higher mean Systemic Lupus International Collaborating Clinics/American College of Rheumatism (SLICC/ACR) damage index scores (SDIs) than adults with SLE (1.7 vs. 0.76; p = 0.008) , as reported by Brunner in the study comparing Canadian inception cohorts with similar backgrounds. Compared with adults, patients with pSLE had significantly more steroid-associated damage, including cataracts (42% vs. 12%; p = 0.0001) and avascular necrosis (21% vs. 5%; p = 0.0003), a potentially debilitating complication of SLE . Age at the time of initial corticosteroid administration was an independent risk factor for osteonecrosis, as recently demonstrated by Nakamura et al. , who found that the rate of corticosteroid-associated osteonecrosis was significantly lower in paediatric patients (6%) than in patients aged 15–20 years (49%) or adult patients (41%) ( p = 0.0001), probably due to their abundant vascularity with growth plates and red marrow. With the increase of disease duration, children with SLE experienced a significantly higher risk of developing renal damage compared to their adult counterparts (45.2% vs. 17.4%; p = 0.023) ( Table 2 ). In line with these results, subjects with pSLE were more likely to have been on dialysis (nearly 20% vs. 6% of the aSLE patients) or have had renal transplantation (nearly 12% vs. 4% of adults with SLE), as concluded by a long-term study conducted on 885 SLE patients, including 90 children . In the same outcome study, pSLE was found to be an independent risk factor for myocardial infarction (OR = 6.8, 95% confidence interval (CI) 2.3–20.02; p < 0.001), confirming that cardiovascular disease is emerging as a significant cause of early morbidity and mortality in patients with pSLE. Of note, previous studies have reported accelerated carotid intimal thickening , and abnormal myocardial perfusion scans , both markers of atherosclerosis, in children and adolescents with SLE. Overall, these results suggest that a preventative focus is especially important for children and adolescents with SLE who face a lifelong burden of considerably increased cardiovascular risk due to the disease itself or its treatment . As there is a high degree of morbidity in pSLE compared with aSLE , a careful monitoring of damage accrual is of paramount importance. Although the SDI has proven suitable to assess damage in patients with pSLE, it does not capture some forms of damage that are unique to children and adolescents such as growth failure and delayed puberty . Furthermore, SDI covers only irreversible damage and does not take into account the ability of children to recover and regenerate from damage to a greater extent than adults. A modified version of the SDI for use in pSLE was therefore developed through evidence-based scrutiny of potential sources of damage in 1015 patients . Growth failure and delayed puberty were recorded in 15.3% and 11.3% of patients, respectively, and were included as additional organ systems/domains to the original SDI . The negative effect of glucocorticoids on linear growth prior to the closure of growth plates, together with the modification of body image induced by treatment, may represent a major psychological burden especially in adolescents building their self-esteem and may affect treatment compliance. Although delayed puberty is a temporary phenomenon, it may have irreversible consequences due to its interference with physiological events such as the growth spurt or bone mass accretion (which are both already potentially compromised by steroid treatment), potentially leading to final short stature and premature osteoporosis.
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