Lupus in children

Epidemiology

Among all patients with SLE, it is estimated that 10%-20% have onset in childhood. Definition of childhood-onset, or pediatric SLE (pSLE), however, varies by study as the age thresholds used can be quite variable. In general, the majority of pSLE cases develop in adolescents, while prepubertal onset is relatively rarer.

Limited data is available on incidence and prevalence of lupus in children. A recent review of the Medicaid database estimated an overall SLE prevalence of 9.73 per 100,000 children in the United States. Incidence rate was calculated at 2.22 cases/100,000/year, substantially higher than a prior estimation of 0.28 based on data gathered by a Canadian disease registry. This difference may be explained by differences in racial composition, or possibly increasing frequency of pediatric SLE over time, as has been suggested in studies of SLE in adults.

In the Medicaid study, non-White children were disproportionately affected at higher rates, consistent with what has been reported in adults with SLE. Among the racial groups, Asian children had the highest prevalence of both SLE and lupus nephritis at 23.79 and 11.21, respectively, followed by African-American, Native American, and Hispanic children. Non-Caucasian children with SLE also have younger age of onset and higher prevalence of renal disease. In a large study of hospital admissions for pediatric SLE, African-American, and Hispanic children had higher rates of end-stage renal disease and death; Hispanic patients also had longer lengths of stay and more readmissions. Socioeconomic status may play a role in some of the observed racial and ethnic differences, but these factors remain inadequately studied at this point.

Females are also disproportionately affected by pediatric SLE, similar to what is reported in adult-onset SLE. However, the female-to-male ratio is lower in children than in adults, with estimates ranging from 3.6-5.3 to 1. Most studies have suggested a trend toward less skewed sex ratios in children with prepubertal disease, and the sex ratio is nearly even in infantile-onset SLE.

In contrast to SLE, subacute cutaneous lupus erythematosus and other cutaneous-limited forms of lupus are extremely rare in children, with literature mostly limited to case reports.

Clinical manifestations

Hematologic, musculoskeletal, and cutaneous manifestations are the most common presenting features in pSLE, each observed in 55%-70% of cases. Initial presentations of SLE in children are often severe, with severe organ involvement in 40% of children at onset. In one cohort of 256 patients followed for a mean of 3.5 years, 3 of 6 deaths occurred at first presentation.

Initial presenting features also often include constitutional symptoms, such as fever and fatigue. Raynaud phenomenon is noted at presentation in 10%-14% of children with SLE.

Hematologic manifestations most typically include Coombs-positive hemolytic anemia, thrombocytopenia, and leukopenia. Hemolytic anemia is more common in children with SLE as compared to adults. Antiphospholipid antibodies are found in 30%-50% of pediatric SLE cases. Children with antiphospholipid syndrome appear to be at higher risk for thrombotic events, particularly venous thrombosis, as compared to adults.

In contrast to adult SLE, antidsDNA antibodies are found in high frequency (61%-93%) in pediatric SLE. The strength of association between anti-DNA antibodies and renal disease may also be stronger in children than in adults. Rheumatoid factor is comparatively rare in pediatric SLE. Antihistone and antiribosomal P antibodies are also more common in children with SLE, while other autoantibody profiles are generally similar between children and adults. Although the frequencies of Ro/SSA and La/SSB antibodies are not significantly different in pediatric and adult SLE, sicca symptoms are less common in children.

Hypocomplementemia is noted in >70% of children with SLE. Inherited complement deficiencies are more commonly seen in pediatric SLE, as typically complement deficiency is associated with early onset of autoimmune manifestations. Other laboratory manifestations are generally similar to those seen in adults; both hyper- and hypogammaglobulinemia are reported.

Arthritis in pediatric SLE is usually nonerosive, most commonly symmetric and affecting knees, fingers, wrists, and ankles. There is some evidence that arthritis is less common in pediatric disease. In most cases, if present, the arthritis is noted at initial diagnosis. Thus, joint symptoms that develop more than 1 year after disease onset should prompt consideration of other causes, especially avascular necrosis. Children may be relatively protected from osteonecrosis, however; one prospective study found significantly lower rates of osteonecrosis in pediatric patients (defined as <15 years of age) as compared to adolescent and adult patients, despite receiving higher daily corticosteroid doses.

Cutaneous manifestations are similar to those seen in adults; malar rash, vasculitis, photosensitivity, and oral ulcers are most common ( Fig. 55.1 ). Alopecia is also seen in 10%-29% of children with SLE ( Fig. 55.2 ). Chronic idiopathic urticaria is also associated with SLE and can sometimes be a presenting feature. In one study, children with a new diagnosis of SLE were twice as likely as non-SLE controls to have a history of chronic urticaria.

Renal involvement occurs at significantly higher rates in children and adolescents with SLE as compared to adults. Prevalence of nephritis in pediatric SLE is estimated between 37% and 55%, and, if present, is found at initial diagnosis or within 2 years of disease onset in 90% of patients. The distribution of nephritis histological class mirrors that seen in adults; more than half of these children will have proliferative (WHO class III-IV) disease. Renal disease in children is more severe than that in adults, and is a major cause of morbidity. As in adults, however, membranous lupus nephritis is associated with better outcome.

Neuropsychiatric disease is a concerning feature that affects 15%-30% of children with SLE. As with other severe organ involvement in pSLE, onset typically occurs in early in the course. Headaches, seizures, and psychosis are the most commonly reported symptoms. Chorea is rare but seen more often in children than adults. Overt lupus cerebritis presenting with these features is easily recognized; however, cognitive impairment and depression/mood disorders due to SLE are often overlooked. Depression can be the primary initial manifestation of pSLE, although it can be hard to distinguish depression due to autoimmunity in an adolescent population with generally high rates of mood disorders. A decline in school performance and depressive symptoms can also be related to a number of noninflammatory causes that must be considered. These include difficulty adjusting to chronic illness, missed school days due to medical appointments, and glucocorticoid side effects. Regardless of etiology, fatigue, and depression are associated with lower quality of life scores in pSLE.

Cardiac manifestations (myocarditis, pericarditis, or endocarditis) are present in nearly 20% of pSLE, again significantly more frequent as compared to adult-onset SLE, with most affected patients showing evidence of involvement at diagnosis. Coronary arteritis and dilation is a reported but uncommon complication in pSLE. Myocardial infarction is rare in pSLE and may or may not be associated with antiphospholipid syndrome.

Gastrointestinal involvement in pSLE includes mesenteric vasculitis, autoimmune hepatitis, and lupus enteritis. Elevated transaminase levels have been reported in nearly 50% of pSLE patients.

Macrophage activation syndrome (MAS) is a serious complication of SLE that may be underrecognized. In a recent cohort study, 9% of pSLE patients developed MAS, with the majority of episodes occurring at initial SLE presentation. MAS is more commonly associated with systemic juvenile idiopathic arthritis (SJIA) but the severity of illness may be greater in SLE than in SJIA, with higher rates of ICU admission, need for mechanical ventilation, and longer hospital stays. The mortality of MAS development in pSLE may be as high as 11%. Presence of arthritis and use of hydroxychloroquine may be protective factors against the development of MAS.

Familial SLE

Though typically thought to be of multigenic or oligogenic origin, familial cases of SLE demonstrate the potentially strong contribution of single gene variants to lupus pathogenesis. In many instances of familial lupus, the autoimmune phenotype develops early in life. Inherited deficiencies of complement are the best known examples of this. Patients with deficiency of C1q have >90% lifetime risk of developing SLE; in these cases, onset of SLE features occurs at a median age of 6 years.

Detailed examination of families with multiple affected members has yielded new insights into the pathogenesis of SLE. In addition to complement factors, other contributory genes identified through analysis of families with SLE or lupus-like diseases include TREX1 , DNASE1L3 , and PRKCD , among others. The implicated pathways include those involved in sensing DNA damage, clearance of DNA in apoptosis, and B cell signaling. As most cases of familial SLE do not have an identified genetic mutation, it can be expected that more gene variants important for lupus pathogenesis will be discovered in future studies of these families.

The genetic basis of SLE and monogenic forms of lupus are discussed in greater depth elsewhere ( 10, 11 ).