Abstract
Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition. This disease is characterized by simultaneous or sequential organ and system involvement, with unpredictable flare and high levels of morbidity and mortality. Racial/ethnic background, socioeconomic status, cost of medications, difficulty accessing health care, and poor adherence seem to impact lupus outcomes and treatment response. In this article, the management of cSLE patients is updated. Regarding pathogenesis, a number of potential targets for drugs have been studied. However, most treatments in pediatric patients are off-label drugs with recommendations based on inadequately powered studies, therapeutic consensus guidelines, or case series. Management practices for cSLE patients include evaluations of disease activity and cumulative damage scores, routine non-live vaccinations, physical activity, and addressing mental health issues. Antimalarials and glucocorticoids are still the most common drugs used to treat cSLE, and hydroxychloroquine is recommended for nearly all cSLE patients. Disease-modifying antirheumatic drugs (DMARDs) should be standardized for each patient, based on disease flare and cSLE severity. Mycophenolate mofetil or intravenous cyclophosphamide is suggested as induction therapy for lupus nephritis classes III and IV. Calcineurin inhibitors (cyclosporine, tacrolimus, voclosporin) appear to be another good option for cSLE patients with lupus nephritis. Regarding B-cell-targeting biologic agents, rituximab may be used for refractory lupus nephritis patients in combination with another DMARD, and belimumab was recently approved by the US Food and Drug Administration for cSLE treatment in children aged > 5 years. New therapies targeting CD20, such as atacicept and telitacicept, seem to be promising drugs for SLE patients. Anti-interferon therapies (sifalimumab and anifrolumab) have shown beneficial results in phase II randomized control trials in adult SLE patients, as have some Janus kinase inhibitors, and these could be alternative treatments for pediatric patients with severe interferon-mediated inflammatory disease in the future. In addition, strict control of proteinuria and blood pressure is required in cSLE, especially with angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use.
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Belimumab, a monoclonal antibody that blocks the binding of soluble B lymphocyte stimulator to B cells, was recently approved by the US Food and Drug Administration for childhood-onset systemic lupus erythematosus (cSLE) treatment in children aged >5 years. |
Calcineurin inhibitors (cyclosporine, tacrolimus, voclosporin) appear to be a good option for cSLE patients with lupus nephritis. |
Anti-interferon therapies (sifalimumab and anifrolumab) have shown beneficial results in adult SLE patients, as have Janus kinase inhibitors, and could in the future be an alternative treatment for pediatric patients with severe interferon-mediated inflammatory disease. |
New therapies targeting CD20, such as atacicept and telitacicept, seem to be other promising drugs for SLE patients. |
1 Introduction
Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition. This chronic condition is characterized by simultaneous or sequential organ and system involvement, with unpredictable flare and high morbimortality [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24].
cSLE presentation and severity may vary according to genetic background and socioeconomic status [14]. This condition may be associated with irreversible accrual of damage, reduced health-related quality of life, and diminished life expectancy, mainly due to infections and recurrence of disease activity [18, 19].
The hallmark of cSLE is the wide spectrum of clinical and laboratory abnormalities, particularly with the production of multiple autoantibodies against histone, nonhistone, cytoplasm, and nuclear proteins, and a marked increase in proinflammatory cytokines [11, 12, 14,15,16]. The clinical cSLE presentation spectrum is very diverse, varying from acute, severe, life-threatening disease to chronic condition with an intermittent or continuous course, and is rarely associated with spontaneous remission without treatment [1, 2, 11].
A more aggressive course and disease flares associated with higher morbidity and mortality rates have been reported at diagnosis and follow-up in cSLE patients compared with adult-onset SLE. Indeed, cSLE patients had a higher prevalence of initial and cumulative multiorgan system involvement, such as nephritis, neuropsychiatric, hematological, and macrophage activation syndrome, than adult-onset SLE patients [13, 25,26,27,28,29,30,31,32,33,34,35]. In contrast, late-onset SLE (> 50 years) patients had the lowest prevalence of constitutional and mucocutaneous manifestations, serositis, and hypocomplementemia compared with cSLE and adult-onset SLE [36]. Children and adolescent patients use the same immunosuppressive agents as adult SLE patients, and generally require more aggressive treatment to achieve disease control than adult SLE populations [1, 2, 25, 28,29,30,31].
Most treatments in cSLE and adult-onset SLE are off-label drugs with recommendations based on inadequately powered studies, therapeutic consensus guidelines, or case series [1, 2, 13, 18, 19]. Racial/ethnic background, cost of medications, poor adherence, and specifically social determinants of health seem to impact lupus outcomes and treatment response [18, 19, 37].
The objective of this narrative review is to provide an update of recent new findings relevant to the management of cSLE, particularly focusing on pharmacological therapy.
2 Pathogenesis
Multiple immunologic abnormalities that occur in SLE patients are molecular targets for treatment. cSLE pathogenesis is a combination of inherited susceptibility, gestational and perinatal-related factors, hormonal changes, and environmental exposures, such as sunlight, drugs, viral infections, and air pollutants (carbon monoxide, sulfur dioxide, nitrogen dioxide, ozone, and particulate matter) [2, 38,39,40,41].
cSLE is also characterized by complex immune dysregulation, involving both innate and adaptative immunity, leading to a loss of self-tolerance followed by a sustained production of pathogenic autoantibodies targeting nuclear antigens [42, 43].
The innate immune system is responsible for a non-specific inflammatory response to pathogens. It includes a range of cells and soluble factors, such as antigen-presenting cells (APC), cytokines, and complement proteins. Dendritic cells are the main APC, and a subgroup, the plasmacytoid dendritic cells (pDC), was significantly higher in SLE patients compared with controls [44] and produce interferon (IFN) type I (IFN-1) and express toll-like receptors (TLR) 7 and 9. The endosomal TLR7 and 9 are able to detect endogenous RNA and DNA antigens [45]. Podocytes in cSLE patients with active nephritis express TLR9 and this was related to proteinuria and increased anti-dsDNA antibody [46]. Antimalarial drugs modulate the TLR7 and TLR9 signaling [47].
Importantly, the IFN-α signature is a central player in SLE pathogenesis [48,49,50,51,52]. IFN-α is elevated in SLE patients, particularly during disease flares, and this cytokine was increased in cSLE patients compared with their first-degree relatives and healthy controls, even in patients receiving medication [51]. IFN drives the inflammation in SLE and activates different cell types in the immune system, contributing to immunological dysregulation [53,54,55]. IFN-I also augments APC function and promotes apoptosis [48]. The IFN-I signature occurred in approximately 60% of cSLE patients and was associated with increased TLR7 expression of cytosolic nucleic acid binding receptors [56]. Associations were also reported between IFN-I and several markers of immune activation, such as complement, and autoantibody production, such dsDNA antibodies, which start and may also maintain SLE disease activity over time [51, 57]. Interestingly, there are now targeted therapies that can potentially modify this IFN signature (see Sect. 5).
Increased apoptosis [32, 42] and impaired clearance of apoptotic debris allow the presentation of nucleic acid self-antigens and perpetuate inflammation in cSLE [58]. The complement system is also relevant in the degradation and removal of chromatin produced during cell death [20, 59,60,61,62]. The loss of tolerance to self-antigens in SLE can also be induced by lymphocyte abnormalities. T-cell functional and phenotypic alterations have implications in SLE pathogenesis [63]. The failure of T cells to produce IL-2 leads to a reduction in regulatory T cells and increased effector T cells, especially the T helper 17 (Th17) phenotype. This imbalance contributes to a pro-inflammatory status in adult-onset SLE and cSLE [64,65,66]. Additionally, changes in T-cell receptors observed in SLE result in hyperactivation of their signaling pathway [64, 67]. Azathioprine and mycophenolate mofetil are immunosuppressive agents that can interfere with T-cell function. Autoantibody production is a hallmark of lupus, and B-cell defects can account for this. B lymphocyte stimulator (BLyS) levels are elevated in cSLE [68] and contribute to a breakdown in self-tolerance. Biological agents, such as rituximab and belimumab, are B-cell pathway-targeting therapy for cSLE.
Another relevant factor in cSLE pathogenesis is genetic background, supported by 10-fold increased concordance in monozygotic compared with dizygotic twins [69]. A recent genomic DNA study including 2001 multi-ethnic SLE patients demonstrated an inverse association between age and genetic risk score involving genes outside of the HLA complex [70]. cSLE is usually a polygenic disease and more than 80 different genes in genome-wide association studies were associated with SLE [71], mainly affecting multiple pathways of the immune system [42, 64, 72].
Furthermore, single gene defects associated with cSLE are very rare [73], involving different immune pathogenetic pathways, such as the complement system, phagocyte oxidase system, apoptosis, nucleic acid repair, DNA degradation, DNA sensing, type I IFN, and B-cell development [74, 75]. Inborn errors of immunity are caused by monogenic mutations, resulting in loss or gain of function of the encoded protein, and may present as increased susceptibility to infectious diseases, allergic, malignant, autoinflammatory and autoimmune conditions [76].
Genetic analysis to assess monogenic lupus (whole exome or whole genome sequencing) is very important to improve the knowledge of the genetic basis and increase options for new drug targets and biomarker development [77], and therefore should be considered for cSLE patients with early onset of lupus manifestations (mainly in infants and toddlers with cSLE) [78]. Patients with the gene defect have a specific disease presentation and progression [79], such as recurrent infection and prominent cutaneous manifestation, requiring personalized management.
3 Childhood-Onset Systemic Lupus Erythematosus (cSLE) Stratification and New Validated Classification Criteria
Lupus is a very heterogeneous disease and the response to treatment is very difficult to predict. This heterogeneity is one of the reasons for the high failure rate of target therapy trials. Stratification schemes and accurate classification criteria of cSLE patients represent potential ways of refining cSLE clinical trials [80].
Studies evaluating cSLE stratification at disease onset and during the disease course have been reported to differentiate clinical and laboratory abnormalities according to age and diagnostic delay [20,21,22, 81, 82].
A large, retrospective, multicenter cohort study in Brazil assessed demographic data, clinical manifestations, and laboratory exams at disease diagnosis in three age groups of cSLE: early-onset (< 6 years), school-age (≥ 6 and < 12 years), and adolescent (≥ 12 and < 18 years). Fever, hepatomegaly, and splenomegaly occurred more often in the early-onset group, and weight loss, photosensitivity, and leukopenia/lymphopenia in the adolescent group [20]. Similarly, a British cohort assessed cSLE patients based on age at disease presentation: pre-pubertal (< 7 years), peri-pubertal (8–13 years), and adolescent groups (14–18 years). The adolescents had lower levels of white cell count, and higher frequencies of disease activity, low complement levels, antinuclear antibodies (ANA) positive, and anti-dsDNA titers compared with the other groups [81]. Regarding the accrual damage at the last follow-up, both the Brazilian and British cSLE groups demonstrated that disease damage scores were comparable between the age groups [22, 81].
The Brazilian registry assessed 1533 cSLE patients based on three groups with different periods between the onset of signs/symptoms and the diagnosis. This study revealed cSLE patients infrequently had a shorter time interval to diagnosis (< 1 month) characterized by multisystemic, severe, and active conditions, whereas the majority of cSLE patients had a long-time interval (≥ 3 months) to diagnosis, with mild disease onset [21].
Three classification criteria have been proposed for SLE patients to use in daily clinical practice, research, and clinical trials [83, 84]. The American College of Rheumatology classification criteria modified in 1997 (1997-ACR) are the most universally used for cSLE patients [19, 83]. In 2012, the Systemic Lupus International Collaborating Clinics (2012-SLICC) group published a new set of classification diagnostic criteria, including a stand-alone renal criterion for cSLE patients with biopsy compatible with lupus nephritis and positive ANA or anti-dsDNA antibodies [84].
Studies compared the performance of these two sets of criteria in pediatric lupus populations [85,86,87,88] and reported a higher sensitivity for the 2012-SLICC criteria [85,86,87,88] and higher specificity for the 1997-ACR criteria. A recent meta-analysis established that the 1997-ACR criteria had the best overall performances for cSLE, even if associated with lower sensitivity [89]. In 2019, the European League Against Rheumatism (EULAR) and the ACR developed new classification criteria for systemic lupus preserving the specificity of the 1997-ACR and the sensitivity of the SLICC criteria in adult SLE [90]. The 2019 EULAR/ACR classification criteria proposed weighted criteria grouped in seven clinical and three immunological domains, using ANA positive as a mandatory entry criterion. A score of ≥ 10 classifies a patient as SLE [90].
Three recent reports evaluated 2019-EULAR/ACR classification criteria in cSLE patients. The 2019-EULAR/ACR criteria effectively classify cSLE, irrespective of age, sex, and race, and these new criteria were more sensitive (85% vs 72%) with comparable specificity in youths with SLE compared with the 1997-ACR criteria (83% vs 87%) [91]. Another study showed the same sensitivity for 2019-EULAR/ACR and 2012-SLICC criteria (97.4%) and it was higher compared with the 1997-ACR criteria in cSLE patients (87.2%), with similar specificity between 2012-SLICC and 2019-EULAR/ACR criteria (98.4% and 99.7%, respectively) [92]. Fonseca et al. showed that a 2019-EULAR/ACR total score ≥ 13 was more appropriate to classify Brazilian cSLE patients than the proposed score of ≥ 10 and that 2012-SLICC criteria better scored for cSLE at the first visit and 1-year-follow-up [93].
4 Monitoring Disease Activity and Damage
Disease activity evaluation includes different reliable and valid instruments for use in academic and clinical practice for cSLE [2, 94, 95]. The most important validated overall disease activity scores are Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG), and Medical Global Assessment of Disease Activity (MD Global) [94].
Recently, European evidence-based recommendations for diagnosis and treatment of cSLE and childhood-onset lupus nephritis were established by consensus meetings [96, 97]. One of these recommendations was that all cSLE patients should have disease activity parameters evaluated regularly in clinical practice, using one of the two standardized validated disease activity instruments: SLEDAI 2000 (SLEDAI-2K) or pediatric BILAG index 2004 (pBILAG-2004) [96]. Therefore, disease activity tools should be used at cSLE diagnosis and during the disease course.
There is a new description of low disease activity in SLE patients. The definition of lupus low disease activity state (LLDAS) includes SLEDAI-2K ≤ 4, without any activity in major organ systems and no new features of activity compared with the previous evaluation, Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment ≤ 1; current prednisolone dose ≤ 7.5 mg/day and standard maintenance doses of immunosuppressants and approved biological drugs [98]. Importantly, this parameter has proven to be associated with a decrease in SLE flares, reduced risk of disease damage, and may be used as a treat-to-target approach in daily clinical practice and for future SLE clinical trials [99]. A prospective validation study with 1707 adult SLE patients showed that the percentage of subjects with accrual damage was significantly lower in patients who achieved sustained LLDAS compared with those that never experienced sustained LLDAS (2.9% vs 17.8%) [100]. Further prospective multicenter studies will be necessary to assess LLDAS in cSLE populations.
Recent provisional criteria for global flares in cSLE patients were also established after consensus formation methodology with pediatric rheumatologists and pediatric nephrologists, and defined threshold levels for minor, moderate, and major flares. These criteria included the most important disease activity scores and inflammatory markers, and they are therefore relevant for measuring systemic responses to interventions intended to treat systemic or organ-specific involvements of cSLE patients. One of these criteria was the SLEDAI-based algorithm (0.5 × ΔSLEDAI + 0.45 × Δprotein/creatinine ratio + 0.5 × ΔMD-global + 0.02 × Δerythrocyte sedimentation rate), and flare scores of ≥ 6.4/3.0/0.6 comprised major/moderate/minor flares, respectively. The other criterion was based on BILAG algorithm (0.4 × ΔBILAG + 0.65 × Δprotein/creatinine ratio + 0.5 × ΔMD-global + 0.02 × Δerythrocyte sedimentation rate), and flare scores of ≥ 7.4/3.7/2.2 constituted major/moderate/minor flares, respectively [101]. These criteria are relevant instruments for future use in clinical trials, allowing longitudinal assessment of cSLE patients and measurement of overall disease course since existing treatments used in cSLE are not uniformly effective in reducing disease activity [101].
In addition, the same international consensus with pediatric rheumatologists and nephrologists also established a provisional index of clinically relevant improvement in cSLE. This is an important instrument to assess response to treatment and to classify the degree of improvement as minor, moderate, or major [102].
Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score evaluates cumulative damage, indicating an overall measurement of disease activity and severity in SLE patients. This score is validated for pediatric lupus patients and has been demonstrated to be a valid and reliable instrument for cSLE [2]. It is a mainly disease-related outcome, while treatment with glucocorticoids, immunosuppressive and biological agents are also risk factors for increased damage score [2, 22].
A pediatric version of SDI is also available for clinical practice in cSLE, including two additional domains: growth failure and delay in secondary sexual characteristics [103]. European evidence-based recommendations for diagnosis and treatment of cSLE also suggested that patients with cSLE should have cumulative damage assessed yearly using a standardized damage parameter, primarily using pediatric SDI [96].
The SDI instrument is the sum of SDI item scores. The frequency of SDI score ≥ 1 ranged from 28% to 52% of cSLE populations, generally evidenced after 2–4 years of diagnosis [104, 105]. A recent, international multicenter study including 1048 cSLE patients with a mean disease duration of 3.8 years evidenced that almost half the patients had disease-related damage measured by SDI score. The most frequently scored items were proteinuria, scarring alopecia, and cognitive impairment [106]. Neuropsychiatric and renal involvements were the main predictors of higher damage accrual over time in another report [107].
Two other prospective studies from Canada and the Netherland assessed the long-term outcomes of adult SLE patients with pediatric onset. A longitudinal damage study with 473 SLE patients showed that baseline features, Afro-Caribbean ethnicity, short diagnosis lag time, and the presence of major organ and system involvements (lupus nephritis class III/V, cerebrovascular accidents, vasculitis, alveolar hemorrhage, and/or myocarditis) were significantly associated with more damage [108]. Another study of 111 cSLE patients with median disease duration of 20 years demonstrated that acute cerebrovascular accident, renal transplantation, replacement arthroplasties, and acute myocardial infarction were evidenced in the ages of 20 years, 24 years, 34 years, and 39 years, respectively [109]. Since the mortality rate of SLE has progressively decreased in the last decades [110], the prevention of organ damage is one of the main goals in the management of cSLE patients, including early diagnosis, multidisciplinary approach, and aggressive treatment.
5 Management Data and Drugs for cSLE
The goals of cSLE treatment are to alleviate signs and symptoms, control disease activity, minimize drug-induced adverse events, prevent long-lasting damage, and improve health-related quality of life. Immunomodulation and immunosuppression are the main focus of pharmacological management, and specific therapy should be individualized according to the manifestations and severity of the disease. cSLE management requires a multidisciplinary and multiprofessional team, led by a qualified pediatric rheumatologist who can co-ordinate the patient’s support with all pediatric subspecialties [1, 2, 13]. Presently, there is a lack of high-quality evidence of multinational clinical trials, and therefore the majority of treatments have been adapted from adult protocols and are mainly established by clinical experience, clinical practice guidelines, and retrospective case series [2, 13, 66, 111].
Health quality measures are tools used by care management organizations to provide high-quality health care for patients [112]. International consensus recommendations for care of cSLE patients included nine quality indicators: diagnostic testing, education of cardiovascular risk and lifestyles, lupus nephritis, bone health, ophthalmologic examination, medical transition to adult clinic care, pregnancy, medication management, and immunization [113]. A further multicenter and multinational study including 483 cSLE showed that larger tertiary pediatric rheumatology centers tended to meet these cSLE quality indicators and offer standards of medical care more often than smaller centers. Notably, assessment of bone mineral density in patients exposed to glucocorticoids ranged widely among the centers involved (7–90%), and some centers reported low accessibility to kidney biopsies [114].
5.1 General Treatment
General management practices for cSLE patients include sunscreen protection, a well-balanced diet with low salt and adequate calcium consumption, and immunization against common pathogens [2]. Due to immune dysregulation and immunosuppressive treatment, cSLE patients have a marked increased risk of infections. Indeed, infections are one of the most common causes of mortality and can induce a disease flare in these patients [22]. Therefore, immunization is a powerful tool to reduce the burden of infectious diseases in the clinical management of cSLE and is recommended to be undertaken prior to the initiation of immunosuppressive treatment for all patients. Routine non-live vaccinations are strongly suggested for all children and adolescents with cSLE, such as influenza, tetanus, hepatitis A and B, meningococcal, pneumococcal, quadrivalent human papillomavirus vaccinations, and COVID-19 [115, 116]. Live attenuated immunizations (such as varicella-zoster; measles, mumps and rubella; and yellow fever vaccines) are generally not indicated for immunosuppressed cSLE patients [2]; however, no severe events with live-attenuated viruses were reported in a case series of vaccinated cSLE patients under immunosuppressive agents, after the measles, mumps and rubella and varicella-zoster booster vaccinations [117]. Non-live vaccines against COVID-19 may be used in young and adult patients with rheumatic diseases under immunosuppressive/immunomodulating therapy [118]. The potential risks of vaccines against COVID-19 remain unknown for adult-onset SLE patients and the optimal dose for efficacy may be different from that in healthy subjects, however, the risks of not receiving the immunization are far greater currently [119]. Preliminary data for one COVID-19 immunization (messenger RNA vaccine) in a placebo-controlled trial of 2200 adolescents aged 12–15 years showed 100% efficacy and a strong immune response [120]. This may be relevant to efforts to control the pandemic, since this group of patients may have a role in viral transmission [121] and a distinct phenotype from adults with less symptomatic disease [122]. Further studies to confirm these data and to assess the medium and long-term effectiveness and safety of the COVID-19 vaccine in pediatric rheumatic diseases are eagerly awaited since widespread vaccination is the most efficacious tool to fight against this global pandemic. Table 1 illustrates vaccines that are indicated and contraindicated in the clinical practice of immunosuppressed cSLE patients.
Strict control of blood pressure is periodically required. A recent study reported arterial hypertension in approximately one-third of cSLE patients, almost 3 years after the disease onset. In multivariate analysis, lupus nephritis, obesity, and high frequency of extra-renal disease activity were independent predictors of arterial hypertension at baseline [123]. Prompt adjuvant treatment of arterial hypertension and proteinuria should be recommended for all cSLE patients [96]. Renin–angiotensin–aldosterone system blockade antihypertensive and antiproteinuric effects are particularly important in SLE management [124]. Proteinuria is a strong predictor of long-term renal outcomes [125]; consequently, angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) use is considered a renoprotective strategy [126] and recommended for all SLE patients with arterial hypertension or with proteinuria (urine protein:creatinine ratio > 50 mg/mmol) [124, 127, 128]. A recent study demonstrated that the combination of ACE-I and ARB had good tolerability and was without significant adverse events in adult SLE, such as worsening of renal function and hyperkalemia [126].
Physical activity should be recommended for cSLE treatment on a routine basis [129]. Pinto et al. showed that cSLE patients, including those with mild and inactive disease, had impaired aerobic capacity and reduced health-related quality of life parameters compared with healthy controls matched by physical inactivity, age, sex, and body mass index [130].
Management issues related to mental health, particularly anxiety, depression, and ineffective family coping, are frequent in children and adolescents with cSLE or lupus nephritis patients and may impact their health-related quality of life [131, 132]. Although there is a lack of controlled studies assessing mental issues in cSLE, studies report depression and anxiety symptoms to be present in 37% and 30% of patients, respectively [133], and to be more frequent during the induction phase of the treatment [131]. Identifying targets for improving mental health care, such as developed mental health training for pediatric rheumatologists and integration of medical and mental health services, was proposed by CARRA (Childhood Arthritis and Rheumatology Research Alliance) [132]. Therefore, monitoring and referrals for mental health staff in cSLE patients are warranted.
5.2 Immunomodulation and Immunosuppression
Antimalarial drugs are the backbone of the immunomodulatory regimen used to treat cSLE patients and are an effective steroid-sparing treatment [134]. The benefits of hydroxychloroquine (HCQ) on autoimmune disorders have been known for many decades [47], and this drug may interfere in the inhibition of TLR7 and TLR9 signaling, dendritic cell function, and binding of antiphospholipid antibody-β2-glycoprotein I complexes [135]. The Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations for diagnosis and treatment of cSLE suggest that all cSLE patients should be on HCQ regularly [96], and the HCQ prescription is considered a quality measure indicator for cSLE treatment [136]. In line with these recommendations, a recent retrospective inception cohort with 473 cSLE patients showed that antimalarial exposure 6 months before each visit protected against an increase in SDI damage score [108]. Another study observed that current HCQ monotherapy was associated with the absence of damage (SDI score of 0) in a cohort of adults with cSLE that assessed long-term clinical outcomes [109].
Retinopathy is the most important adverse event of HCQ. The 2016 revision recommendations on screening for HCQ retinopathy from the American Academy of Ophthalmology proposed a baseline ophthalmologic examination (automated visual fields and spectral-domain optical coherence tomography) for all lupus patients during the first year of starting HCQ and annual screening after 5 years. The main risk factors for retinopathy are daily dosage > 5 mg/kg (with an additional risk annually), renal disease and underlying retinal disease [137]. In contrast, many pediatric practitioners recommend annual eye screening for cSLE patients, reinforced by the SHARE guidelines, especially for those under HCQ treatment [96].
Glucocorticoids (GC) are an effective anti-inflammatory and immunosuppressive drug for cSLE therapy, often necessary for rapid disease control, and should be limited in dose and duration to what is clinically necessary. The most important GC mechanism of action is the activation of cytosolic glucocorticoid receptors, interfering in the transcription of nuclear factor-kB and decreasing the synthesis of pro-inflammatory proteins. Non-genomic pathways of GC also play an important role in the anti-inflammatory effects, especially with high-dose pulse glucocorticoid therapy [138]. In addition, glucocorticoids stimulate apoptosis in many cell types, including pDC. However, chronically stimulated pDC through TLR7 and 9 are more resistant to glucocorticoid-induced apoptosis and this contributes to the reduced therapeutic activity of oral glucocorticoids. In contrast, intravenous methylprednisolone pulse therapy may normalize the IFN signature and is associated with a reduction in the number of circulating pDC [139]. Prolonged and high-dose use of GC should be strictly avoided due to the significant adverse events, particularly in children and adolescents [2]. Indeed, a recent longitudinal study demonstrated that adults with childhood-onset disease had significantly higher steroid-related damage compared with those who had disease onset after 18 years old (OR 1.7, 95% CI 1.1–2.8) [140]. Dosages of GC ≥ 7.5 mg/day were associated with cataract, osteoporotic fractures, and cardiovascular damage in SLE patients [141]. Furthermore, the glucocorticoid effect on chondrocytes and the hypothalamic-pituitary-gonadal axis interferes in the developmental stage of adolescence and impacts final height and puberty [142,143,144]. In a retrospective cohort of 97 cSLE patients, 23% of the participants were classified as having short final height and they had a higher cumulative corticosteroid dose compared with those with normal final height [143]. Rygg et al. showed that delayed pubertal onset was observed in 15.3% of females with cSLE and 24% of males [144].
Specific immunosuppressives should be customized for each patient based on disease flare and cSLE severity [2]. Lupus nephritis is the leading cause of morbidity in cSLE patients [22, 109] and immunosuppressive therapy includes induction and maintenance. Recently, the SHARE initiative [97] and Latin American Group for the Study of Lupus (GLADEL) and Pan-American League of Associations of Rheumatology (PANLAR) published recommendations for childhood-onset lupus nephritis treatment [18]. For lupus nephritis classes I and II, low-dose prednisone and antimalarials are first-line therapy [2], and disease-modifying antirheumatic drugs (DMARDs) should be used in the event of persistent proteinuria or failure to taper GC after 3 months [97]. For lupus nephritis classes III and IV, mycophenolate mofetil or intravenous cyclophosphamide (IVCYC) in combination with corticosteroids are recommended as induction therapy, while mycophenolate mofetil or azathioprine are suggested as maintenance therapy for 3 years [18, 97]. For pure membranous lupus nephritis (class V), the SHARE expert group suggests induction treatment with mycophenolate mofetil in combination with low-dose oral prednisone, and mycophenolate mofetil or azathioprine as maintenance therapy [97].
Nevertheless, cSLE patients with refractory disease or with a severe adverse event to standard therapies require additional treatment [2, 66, 97, 134]. Although there is limited evidence for rituximab use in children and adolescents with cSLE, a recent systematic review suggested that this B-cell-targeting biologic agent was safe and improved disease activity, serum and urine disease activity markers, and reduced GC dose in cSLE patients [145]. The SHARE group also recommended rituximab for refractory lupus nephritis patients in combination with another DMARD [97]. Recently, rituximab was also effective as second-line therapy for refractory autoimmune hematological disease in cSLE patients [146], and in a small case series of childhood-onset lupus erythematosus panniculitis [147].
Specific immunosuppression should also be matched to disease manifestations, not just flare, and overall severity. The combination of cyclophosphamide and rituximab has been reported more widely in cSLE [148]. Another case report involving three cases demonstrated that a combination of rituximab and abatacept was a strategy for repetitive B-cell depletion in children and adolescents with severe autoimmune diseases, including two cSLE patients [149].
Belimumab is a monoclonal antibody that blocks the binding of soluble BLyS to B cells. This B-cell pathway-targeting agent was recently approved by the US Food and Drug Administration (FDA) for cSLE treatment in children > 5 years of age [134, 150]. Importantly, a randomized, double-blind, placebo trial evaluated the efficacy and safety of intravenous belimumab (10 mg/kg) plus standard therapy versus placebo in cSLE patients. The main exclusion criteria were active neuropsychiatric lupus, acute severe lupus renal involvement, and prednisone > 1.5 mg/kg/day. A greater proportion of patients receiving this biologic therapy met the primary efficacy endpoint of SLE responder index (SRI4) response rate (52.8% vs 43.6%; OR 1.49 [95% CI 0.64–3.46]). The improvement in Pediatric Rheumatology International Trials Organization/American College of Rheumatology (PRINTO/ACR) response using 50 definitions was also significantly higher in the belimumab group (60.4% vs 35.0%; OR 2.74 [95% CI 1.15–6.54]). Serious adverse effects were observed in 17% of the belimumab group and 35% of the placebo group, and none of them developed anti-belimumab antibodies. However, a limitation of this study was the small sample size to identify a statistically significant difference in the primary outcome [151]. The use of belimumab for cSLE patients was reported by 11% (18/161) of surveyed Latin America Pediatric Rheumatologists [19]. Further multicenter and multinational studies with this biologic drug in a large cSLE population will be required.
There are new therapies targeting CD20 in SLE patients. Atacicept and telitacicept are anti-CD20 monoclonal antibody agents that inhibit both BAFF (B-lymphocyte Activating Factor of the tumor necrosis factor Family) and APRIL (A PRoliferation-Inducing Ligand), both are relevant B-cell regulator cytokines, and anti-BAFF and APRIL therapies seem to be promising drugs for SLE patients [152].
Anti-IFN therapies, such as sifalimumab (anti-IFN-α monoclonal antibody) and anifrolumab (a monoclonal antibody that binds to a type I IFN receptor) have shown beneficial results in phase II randomized control trials in adult SLE patients with moderate-severe disease versus placebo in addition to standard-of-care medications, without severe nephritis and neuropsychiatric involvement [153,154,155]. A recent case report of three cSLE patients allergic to rituximab demonstrated that ofatumumab, a fully humanized anti-CD20 monoclonal antibody, was a safe, well tolerated, and effective alternative for B-cell depletion [156]. Another report suggested Janus kinase (JAK) inhibitors as an alternative treatment for pediatric patients with severe IFN-mediated inflammatory disorders, including cSLE patients, reducing progressively inflammatory markers, IFN score, and inducing upregulation of the DNA repair pathway [157].
Calcineurin inhibitors (cyclosporine, tacrolimus, voclosporin) have both immunomodulatory and non-immune-mediated roles in treating SLE. They inhibit T-cell proliferation in addition to non-immunological effects that reduce proteinuria, including podocyte cytoskeleton stabilization and afferent arteriole vasoconstriction [158]. According to the SHARE recommendation, tacrolimus and ciclosporin can be an option for selected lupus nephritis patients [97].
Calcineurin inhibitors have been studied within a multi-target treatment in proliferative lupus nephritis, particularly in the Asian population. In a randomized controlled trial including 368 SLE patients also treated with intravenous methylprednisolone pulse therapy and oral prednisone, the overall response was higher in SLE patients receiving 24 weeks of mycophenolate mofetil (1 g/day) plus tacrolimus (4 mg/day) versus those receiving intravenous cyclophosphamide (84% vs 63%). The incidence of adverse events was similar in both groups [159]. Voclosporin has been studied in a phase II, multicenter, randomized, double-blind, placebo-controlled trial of induction therapy for lupus nephritis, in combination with mycophenolate mofetil and rapid corticosteroid tapering. Among 265 geographically diverse lupus nephritis patients at 6 months, the multi-target therapy achieved superior remission rates (27–33%) compared with placebo (19%); however, higher rates of adverse events including death were reported [160]. A meta-analysis of 45 randomized trials involving 4222 SLE patients with proliferative lupus nephritis, including children and adolescents with cSLE, also showed higher remission rates with mycophenolate mofetil, calcineurin inhibitors, and their combination than with intravenous cyclophosphamide. Mycophenolate mofetil was the most effective maintenance treatment [161]. Furthermore, in a randomized trial of 28 SLE patients with pure membranous lupus nephritis, greater response rates at 6 months were reported with glucocorticoid and tacrolimus compared with SLE patients with glucocorticoid and mycophenolate mofetil (100% vs 75%) [162]. Therefore, although longer-term outcomes are required, calcineurin inhibitors seem to be a good option for cSLE patients with lupus nephritis.
Table 2 includes the main steroid-sparing immunomodulatory and immunosuppressive agents used in clinical practice for the management of cSLE patients. Serious adverse events are an important aspect of clinical care, counseling, and monitoring for cSLE patients. The most relevant major serious adverse events of immunosuppressive agents are found with azathioprine (infection and bone marrow suppression), methotrexate (hepatotoxicity, gastrointestinal intolerance, and bone marrow suppression), mycophenolate mofetil (infection, bone marrow suppression), cyclophosphamide (infection, decreased ovarian reserve, sperm abnormalities, bone marrow suppression, malignancy), rituximab (infection, infusion reaction, persistent hypogammaglobulinemia), and belimumab (infection) [1, 2, 13, 151, 163] (Table 2).
6 cSLE Prognosis Factors
Knowledge of cSLE prognosis factors is relevant to disease management since predictive factors of the long-term renal outcome at early stages of SLE are important to define clinically relevant targets of drug intervention [164]. Three laboratory or urinalysis tests have been used regularly in clinical practice as noninvasive predictors for cSLE renal involvement: kidney function (serum creatinine levels and measurement of glomerular filtration rate), urinary protein excretion, and glomerular hematuria [15, 165].
Early decrease of 24-hour proteinuria (< 0.8 g/day) is the best predictor of long-term nephritis outcome in SLE patients, based on two previous trials in adult lupus nephritis [166, 167]. Decreased proteinuria at 1 year of follow-up was also the only predictor of renal outcome at 7 years observed in a Latin American SLE group with severe biopsy-proven lupus nephritis [125]. Another study demonstrated that both proteinuria and serum creatinine levels at 1 year were important to predict relevant long-term outcomes in lupus nephritis, while urinalysis did not add value [168].
In cSLE populations, decreased creatinine clearance rate and low C3 complement levels with high serum creatinine levels were associated with end-stage renal disease [169]. A recent study, including 26 previous reports, showed that high serum creatinine (> 1.5 mg/dL) at disease presentation was the major prediction factor for progression to end-stage renal disease [170]. Furthermore, high titers of anti-dsDNA antibodies have modest accuracy to predict lupus nephritis [171].
Novel urinary and serum non-invasive biomarkers were reported to be promising parameters to predict disease outcome, disease activity, and to estimate chronic kidney damage in adult and cSLE patients [165]. A prospective study in cSLE patients with nephritis showed that urinary NGAL (neutrophil gelatinase-associated lipocalin) was a predictor of impaired renal disease activity, contrasting with urinary monocyte chemo-attractant protein 1 (uMCP1) that was a predictor of improved lupus nephritis [172]. Another longitudinal report assessed whether urinary levels of ten biomarkers were related to chronic kidney damage in pediatric lupus nephritis. Renal functional impairment was more evidenced in cSLE patients with persistent high levels of transforming growth factor-β (TGFβ), transferrin, and liver fatty acid-binding protein (LFABP), indicating persistent renal inflammation. Levels of osteopontin and adiponectin measured at the time of kidney biopsy in cSLE patients are good predictors of histological damage with lupus nephritis [173]. Comorbidities in cSLE patients, such as arterial hypertension or diabetes mellitus, may also alter the excretion of urinary and serum non-invasive biomarkers, even in the absence of histologic changes [165]. Further longitudinal and multicenter studies will be necessary to identify and validate these biomarkers for disease activity monitoring and to predict disease severity in different renal histology patterns.
7 Drug Adherence for Adolescents
cSLE patients are mainly in the adolescence period [20]. This transitional phase to adulthood involves several physical and emotional changes [37], and the impact of this complex disease may affect their self-management and self-esteem [174, 175]. In fact, a cSLE study in adolescents and young adults with a semi-structured interview showed that the use of medication served as reminders of their illness and made them feel abnormal [176]. Nonadherence to medication in cSLE adolescents was a relevant issue in clinical practice, reported by 97% of Latin American pediatric rheumatologists [19].
There are factors associated with nonadherence to drug therapy in cSLE and other chronic rheumatic conditions, including forgetfulness, low socioeconomic status, family disruption, polypharmacy, and psychiatric comorbidities [37, 177, 178]. Poor compliance contributes to negatives outcomes and decreases the health-related quality of life [179,180,181]. Scalzi et al. created an online educational program for a cohort of SLE adolescents and young adults. The percentage of drug adherence using web-based education with social media intervention improved significantly from 50 to 92% [182]. A recent systematic review study assessed mobile health technologies to support the management of cSLE and adult SLE, and it demonstrated that currently available instruments were of poor quality and limited functionality [183].
Thus, it is recommended that medication adherence should be checked during the pediatric rheumatologist appointments, especially before any decisions around treatment modifications [2, 96]. Understanding and responding to adolescent demands with a personalized treatment plan and multidisciplinary teams, including psychological/psychiatric support, health education strategies, and adherence interventions may help cSLE teens to increase compliance with treatment [37, 174, 176, 181, 182].
8 Conclusions
cSLE is the prototype of a multisystemic, chronic, inflammatory, and heterogeneous autoimmune condition. This disease is characterized by concomitant or further organ and system involvement, with unpredictable flare and high morbimortality. Whole exome or whole genome sequencing should be considered for cSLE patients to exclude monogenic lupus, particularly in those with early onset of manifestations. Consultation with a geneticist or genetic counselor for such testing should be recommended. Age subgroups may help cSLE stratification at disease onset and during the disease course. The new 2019-EULAR/ACR classification criteria have high sensitivity and high specificity for cSLE, and recent provisional criteria for global flares and a provisional index of clinically relevant improvement have been developed for cSLE patients. Nonadherence to medication in cSLE adolescents was identified as one of the most relevant issues in clinical practice. Belimumab was recently approved by the FDA for cSLE treatment in children aged > 5 years. Recognition that cSLE is a potentially aggressive disease with high morbidity and mortality rates is an essential step towards the development of safer and more efficacious treatments. The treat-to-target principle and tailored medicine approaches are novel paradigms for treatment and should also be standardized for pediatric lupus patients.
References
Silva CA. Childhood-onset systemic lupus erythematosus: early disease manifestations that the paediatrician must know. Expert Rev Clin Immunol. 2016;12:907–10. https://doi.org/10.1080/1744666X.2016.1195685.
Silva CA, Aikawa NE, Pereira RMR, Campos LMA. Management considerations for childhood-onset systemic lupus erythematosus patients and implications on therapy. Expert Rev Clin Immunol. 2016;12:301–13. https://doi.org/10.1586/1744666X.2016.1123621.
Blay G, Rodrigues JC, Ferreira JCO, Leal GN, Gormezano NW, Novak GV, et al. Diffuse alveolar hemorrhage in childhood-onset systemic lupus erythematosus: a severe disease flare with serious outcome. Adv Rheumatol. 2018;58:39. https://doi.org/10.1186/s42358-018-0038-4.
Kahwage PP, Ferriani MPL, Furtado JM, de Carvalho LM, Pileggi GS, Gomes FHR, et al. Uveitis in childhood-onset systemic lupus erythematosus patients: a multicenter survey. Clin Rheumatol. 2017;36:547–53. https://doi.org/10.1007/s10067-016-3534-0.
Silva MF, Ferriani MP, Terreri MT, Pereira RM, Magalhães CS, Bonfá E, et al. A multicenter study of invasive fungal infections in patients with childhood-onset systemic lupus erythematosus. J Rheumatol. 2015;42:2296–303. https://doi.org/10.3899/jrheum.150142.
Ferreira JCOA, Marques HH, Ferriani MPL, Gormezano NWS, Terreri MT, Pereira RM, et al. Herpes zoster infection in childhood-onset systemic lupus erythematosus patients: a large multicenter study. Lupus. 2015;25:754–9. https://doi.org/10.1177/0961203315627203.
Lube GE, Ferriani MPL, Campos LMA, Terreri MT, Bonfá E, Magalhães CS, et al. Evans syndrome at childhood-onset systemic lupus erythematosus diagnosis: a large multicenter study. Pediatr Blood Cancer. 2016;63:1238–43. https://doi.org/10.1002/pbc.25976.
Marques VLS, Gormezano NWS, Bonfá E, Aikawa NE, Terreri MT, Pereira RM, et al. Pancreatitis subtypes survey in 852 childhood-onset systemic lupus erythematosus patients. J Pediatr Gastroenterol Nutr. 2016;62:328–34. https://doi.org/10.1097/MPG.0000000000000990.
Sakamoto AP, Silva CA, Ferriani MPL, Pereira RMR, Bonfá E, Saad-Magalhães C, et al. Characterization of chronic arthritis in a multicenter study of 852 childhood-onset systemic lupus erythematosus patients. Rheumatol Int. 2016;36:1641–8. https://doi.org/10.1007/s00296-016-3564-6.
Sakamoto AP, Silva CA, Saad-Magalhães C, Alencar AN, Pereira RMR, Kozu K, et al. Stevens–Johnson syndrome and toxic epidermal necrolysis in childhood-onset systemic lupus erythematosus patients: a multicenter study. Acta Reumatol Port. 2017;2017:250–5.
Novak GV, Marques M, Balbi V, Gormezano NWS, Kozu K, Sakamoto AP, et al. Anti-RO/SSA and anti-La/SSB antibodies: Association with mild lupus manifestations in 645 childhood-onset systemic lupus erythematosus. Autoimmun Rev. 2017;16:132–5. https://doi.org/10.1016/j.autrev.2016.12.004.
Setoue DN, Pitta AC, Fiorot FJ, Nastri MM, Novak GV, Molinari BC, et al. Symptomatic polyautoimmunity at diagnosis of 1463 childhood-onset lupus: a Brazilian multicenter study. Autoimmun Rev. 2018;17:836–9. https://doi.org/10.1016/j.autrev.2018.03.009.
Thorbinson C, Oni L, Smith E, Midgley A, Beresford MW. Pharmacological management of childhood-onset systemic lupus erythematosus. Pediatr Drugs. 2016;18:181–95. https://doi.org/10.1007/s40272-016-0170-8.
Fiorot FJ, Islabão AG, Pereira RM, Terreri MT, Saad-Magalhães C, Novak GV, et al. Disease presentation of 1312 childhood-onset systemic lupus erythematosus: influence of ethnicity. Clin Rheumatol. 2019;38:2857–63. https://doi.org/10.1007/s10067-019-04631-0.
Miguel DF, Terreri MT, Pereira RMR, Bonfá E, Silva CAA, Corrente JE, et al. Comparison of urinary parameters, biomarkers, and outcome of childhood systemic lupus erythematosus early onset-lupus nephritis. Adv Rheumatol. 2020. https://doi.org/10.1186/s42358-020-0114-4.
Islabão AG, Mota LMH, Ribeiro MCM, Arabi TM, Cividatti GN, Queiroz LB, et al. Childhood-onset systemic lupus erythematosus-related antiphospholipid syndrome: A multicenter study with 1519 patients. Autoimmun Rev. 2020. https://doi.org/10.1016/j.autrev.2020.102693.
Sakamoto AP, Silva CA, da Silva MFC, Lopes AS, Russo GCS, Sallum AME, et al. Initial digital vasculitis in a large multicenter cohort of childhood-onset systemic lupus erythematosus. Rev Bras Reumatol. 2017;57:583–9. https://doi.org/10.1016/j.rbre.2017.09.002.
Pons-Estel BA, Bonfa E, Soriano ER, Cardiel MH, Izcovich A, Popoff F, et al. First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PAN. Ann Rheum Dis. 2018;77:1549–57. https://doi.org/10.1136/annrheumdis-2018-213512.
Ferreira JCOA, Trindade VC, Espada G, Morel Z, Bonfá E, Magalhães CS, et al. Epidemiology and management practices for childhood-onset systemic lupus erythematosus patients: a survey in Latin America. Clin Rheumatol. 2018;37:3299–307. https://doi.org/10.1007/s10067-018-4254-4.
Gomes RC, Silva MF, Kozu K, Bonfá E, Pereira RM, Terreri MT, et al. Features of 847 childhood-onset systemic lupus erythematosus patients in three age groups at diagnosis: a Brazilian multicenter study. Arthritis Care Res. 2016;68:1736–41. https://doi.org/10.1002/acr.22881.
Novak GV, Molinari BC, Ferreira JC, Sakamoto AP, Terreri MT, Pereira RMR, et al. Characteristics of 1555 childhood-onset lupus in three groups based on distinct time intervals to disease diagnosis: a Brazilian multicenter study. Lupus. 2018;27:1712–7. https://doi.org/10.1177/0961203318787037.
Lopes SRM, Gormezano NWS, Gomes RC, Aikawa NE, Pereira RMR, Terreri MT, et al. Outcomes of 847 childhood-onset systemic lupus erythematosus patients in three age groups. Lupus. 2017;26:996–1001. https://doi.org/10.1177/0961203317690616.
Ferriani MPL, Silva MFC, Pereira RMR, Terreri MT, Saad Magalhães C, Bonfá E, et al. Chronic spontaneous urticaria: a survey of 852 cases of childhood-onset systemic lupus erythematosus. Int Arch Allergy Immunol. 2015;167:186–92. https://doi.org/10.1159/000438723.
Anuardo P, Verdier M, Gormezano NWS, Ferreira GRV, Leal GN, Lianza A, et al. Subclinical pulmonary hypertension in childhood systemic lupus erythematosus associated with minor disease manifestations. Pediatr Cardiol. 2017;38:234–9. https://doi.org/10.1007/s00246-016-1504-6.
Esteves GCX, Gormezano NWS, Pereira OL, Kern D, Silva CA, Pereira RMR, et al. Distinct clinical correlates of immune thrombocytopenic purpura at diagnosis of childhood-onset and adult SLE. Mod Rheumatol. 2018;28:649–53. https://doi.org/10.1080/14397595.2017.1386836.
Buff Passone CG, Grisi SJ, Farhat SC, Manna T Della, Pastorino AC, Alveno RA, et al. Complexity of pediatric chronic disease: cross-sectional study with 16,237 patients followed by multiple medical specialties. Rev Paul Pediatr. 2020;38:1–8. https://doi.org/10.1590/1984-0462/2020/38/2018101.
Alveno RA, Miranda CV, Passone CG, Waetge AR, Hojo ES, Farhat SCL, et al. Pediatric chronic patients at outpatient clinics: a study in a Latin American University Hospital. J Pediatr (Rio J). 2018;94:539–45. https://doi.org/10.1016/j.jped.2017.07.014.
Gormezano NWS, Silva CA, Otsuzi CI, Barros DL, Da Silva MA, Sallum AME, et al. Higher prevalence and distinct features of herpes zoster infection in children than adults with systemic lupus erythematosus. Pediatr Infect Dis J. 2015;34:905–7. https://doi.org/10.1097/INF.0000000000000756.
Gormezano NWS, Otsuzi CI, Barros DL, da Silva MA, Pereira RMR, Campos LMA, et al. Macrophage activation syndrome: A severe and frequent manifestation of acute pancreatitis in 362 childhood-onset compared to 1830 adult-onset systemic lupus erythematosus patients. Semin Arthritis Rheum. 2016;45:706–10. https://doi.org/10.1016/j.semarthrit.2015.10.015.
Gormezano NWS, Silva CA, Aikawa NE, Barros DL, da Silva MA, Otsuzi CI, et al. Chronic arthritis in systemic lupus erythematosus: distinct features in 336 paediatric and 1830 adult patients. Clin Rheumatol. 2016;35:227–31. https://doi.org/10.1007/s10067-015-3127-3.
Gormezano NWS, Kern D, Pereira OL, Esteves GCX, Sallum AME, Aikawa NE, et al. Autoimmune hemolytic anemia in systemic lupus erythematosus at diagnosis: differences between pediatric and adult patients. Lupus. 2017;26:426–30. https://doi.org/10.1177/0961203316676379.
Lo MS. Insights gained from the study of pediatric systemic lupus erythematosus. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.01278.
Joo Y Bin, Park SY, Won S, Bae SC. Differences in clinical features and mortality between childhood-onset and adult-onset systemic lupus erythematosus: A prospective single-center study. J Rheumatol. 2016;43:1490–7. https://doi.org/10.3899/jrheum.151129.
Rodsaward P, Chottawornsak N, Suwanchote S, Rachayon M, Deekajorndech T, Wright HL, Edwards SW, Beresford MW, Rerknimitr P, Chiewchengchol D. The clinical significance of antinuclear antibodies and specific autoantibodies in juvenile and adult systemic lupus erythematosus patients. Asian Pac J Allergy Immunol. 2019. https://doi.org/10.12932/AP-211218-0465. Epub ahead of print. PMID: 31012595.
Ramos GF, Ribeiro VP, Mercadante MP, Ribeiro MP, Delgado AF, Farhat SCL, et al. Mortality in adolescents and young adults with chronic diseases during 16 years: a study in a Latin American tertiary hospital. J Pediatr (Rio J). 2019;95:667–73. https://doi.org/10.1016/j.jped.2018.06.006.
Medhat BM, Behiry ME, Sobhy N, Farag Y, Marzouk H, Mostafa N, et al. Late-onset systemic lupus erythematosus: characteristics and outcome in comparison to juvenile- and adult-onset patients—a multicenter retrospective cohort. Clin Rheumatol. 2020;39:435–42. https://doi.org/10.1007/s10067-019-04776-y.
Silva CA. Poor adherence to drug treatment in children and adolescents with autoimmune rheumatic diseases. Rev Paulista Pediatria. 2019;37:138–9. https://doi.org/10.1590/1984-0462/;2019;37;2;00019.
Farhat SCL, Yariwake VY, Veras MM, Braga ALF, Maluf AE, Silva CA. Inhaled ultrafine particles, epigenetics and systemic autoimmune rheumatic diseases. Autoimmun Rev. 2020;19:102640.
Conde PG, Farhat LC, Braga ALF, Sallum AEM, Farhat SCL, Silva CA. Are prematurity and environmental factors determinants for developing childhood-onset systemic lupus erythematosus? Mod Rheumatol. 2018;28:156–60. https://doi.org/10.1080/14397595.2017.1332508.
Alves AGF, de Azevedo Giacomin MF, Braga ALF, Sallum AME, Pereira LAA, Farhat LC, et al. Influence of air pollution on airway inflammation and disease activity in childhood-systemic lupus erythematosus. Clin Rheumatol. 2018;37:683–90. https://doi.org/10.1007/s10067-017-3893-1.
Goulart MFG, Alves AGF, Farhat J, Braga ALF, Pereira LAA, de Faria Coimbra Lichtenfels AJ, et al. Influence of air pollution on renal activity in patients with childhood-onset systemic lupus erythematosus. Pediatr Nephrol. 2020;35:1247–55. https://doi.org/10.1007/s00467-020-04517-3.
Hedrich CM, Smith EMD, Beresford MW. Juvenile-onset systemic lupus erythematosus (jSLE) – Pathophysiological concepts and treatment options. Best Pract Res Clin Rheumatol. 2017;31:488–504. https://doi.org/10.1016/j.berh.2018.02.001.
Tsokos GC. Mechanisms of disease: systemic lupus erythematosus. N Engl J Med. 2011;365:2110–21121. https://doi.org/10.1056/NEJMra1100359.
Jin O, Kavikondala S, Sun L, Fu R, Mok MY, Chan A, et al. Systemic lupus erythematosus patients have increased number of circulating plasmacytoid dendritic cells, but decreased myeloid dendritic cells with deficient CD83 expression. Lupus. 2008;17:654–62. https://doi.org/10.1177/0961203308089410.
Saferding V, Blüml S. Innate immunity as the trigger of systemic autoimmune diseases. J Autoimmun. 2020. https://doi.org/10.1016/j.jaut.2019.102382.
MacHida H, Ito S, Hirose T, Takeshita F, Oshiro H, Nakamura T, et al. Expression of toll-like receptor 9 in renal podocytes in childhood-onset active and inactive lupus nephritis. Nephrol Dial Transpl. 2010;25:2530–7. https://doi.org/10.1093/ndt/gfq058.
An J, Minie M, Sasaki T, Woodward JJ, Elkon KB. Antimalarial drugs as immune modulators: new mechanisms for old drugs. Annu Rev Med. 2017;68:317–30. https://doi.org/10.1146/annurev-med-043015-123453.
Crow MK, Olferiev M, Kirou KA. Type i interferons in autoimmune disease. Annu Rev Pathol. 2019;14:369–93. https://doi.org/10.1146/annurev-pathol-020117-043952.
Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979;301:5–8. https://doi.org/10.1056/nejm197907053010102.
Crow MK, Type I. Interferon in the pathogenesis of lupus. J Immunol. 2014;192:5459–68. https://doi.org/10.4049/jimmunol.1002795.
Postal M, Sinicato NA, Peliçari KO, Marini R, Costallat LTL, Appenzeller S. Clinical and serological manifestations associated with interferon-α levels in childhood-onset systemic lupus erythematosus. Clinics. 2012;67:157–62. https://doi.org/10.6061/clinics/2012(02)11.
Wahadat MJ, Bodewes ILA, Maria NI, van Helden-Meeuwsen CG, van Dijk-Hummelman A, Steenwijk EC, et al. Type I IFN signature in childhood-onset systemic lupus erythematosus: a conspiracy of DNA- and RNA-sensing receptors? Arthritis Res Ther. 2018. https://doi.org/10.1186/s13075-017-1501-z.
Obermoser G, Pascual V. The interferon-α signature of systemic lupus erythematosus. Lupus. 2010;19:1012–9.
Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science. 2001;294:1540–3.
Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197:711–23.
Sakata K, Nakayamada S, Miyazaki Y, Kubo S, Ishii A, Nakano K, et al. Up-Regulation of TLR7-mediated IFN-α production by plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Front Immunol. 2018;9:1957. https://doi.org/10.3389/fimmu.2018.01957.
Rönnblom L, Alm GV. Systemic lupus erythematosus and the type I interferon system. Arthritis Res Ther. 2003;5:68–75.
Liphaus BL, Lima L, Palmeira P, Silva CA, Goldenstein-Schainberg C, Carneiro-Sampaio M. Increased sMer, but not sAxl, sTyro3, and Gas6 relate with active disease in juvenile systemic lupus erythematosus. Clin Rheumatol. 2020;39:509–14. https://doi.org/10.1007/s10067-019-04799-5.
Jesus AA, Liphaus BL, Silva CA, Bando SY, Andrade L, Coutinho A, et al. Complement and antibody primary immunodeficiency in juvenile systemic lupus erythematosus patients. Lupus. 2011;20:1275–84. https://doi.org/10.1177/0961203311411598.
Macedo ACL, Isaac L. Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway. Front Immunol. 2016. https://doi.org/10.3389/fimmu.2016.00055.
Liphaus BL, Umetsu N, Jesus AA, Bando SY, Silva CA, Carneiro-Sampaio M. Molecular characterization of the complement C1q, C2 and C4 genes in Brazilian patients with juvenile systemic lupus erythematosus. Clinics. 2015;70:220–7. https://doi.org/10.6061/clinics/2015(03)12.
Jesus AJ, Silva CA, Carneiro-Sampaio M, Sheinberg M, Mangueira CL, Marie SK, et al. Anti-C1q antibodies in juvenile-onset systemic lupus erythematosus. In: Annals of the New York Academy of Sciences. Blackwell Publishing Inc.; 2009. pp. 235–8. https://doi.org/10.1111/j.1749-6632.2009.04675.x.
Mak A, Kow NY. The pathology of t cells in systemic lupus erythematosus. J Immunol Res. 2014. https://doi.org/10.1155/2014/419029.
Tsokos GC, Lo MS, Reis PC, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12:716–30. https://doi.org/10.1038/nrrheum.2016.186.
Singla S, Wenderfer SE, Muscal E, Sagcal-Gironella ACP, Orange JS, Makedonas G. Changes in frequency and activation status of major CD4+ T-cell subsets after initiation of immunosuppressive therapy in a patient with new diagnosis childhood-onset systemic lupus erythematosus. Front Pediatr. 2017. https://doi.org/10.3389/fped.2017.00104.
Smith EMD, Lythgoe H, Midgley A, Beresford MW, Hedrich CM. Juvenile-onset systemic lupus erythematosus: update on clinical presentation, pathophysiology and treatment options. Clin Immunol. 2019. https://doi.org/10.1016/j.clim.2019.108274.
Enyedy EJ, Nambiar MP, Liossis SNC, Dennis G, Kammer GM, Tsokos GC. Fcε receptor type I γ chain replaces the deficient T cell receptor ζ chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44:1114–21. https://doi.org/10.1002/1529-0131(200105)44:5%3c1114::AID-ANR192%3e3.0.CO;2-B.
Hong SD, Reiff A, Yang HT, Migone TS, Ward CD, Marzan K, et al. B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients. Arthritis Rheum. 2009;60:3400–9. https://doi.org/10.1002/art.24902.
Deafen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992;35:311–8.
Dominguez D, Kamphuis S, Beyene J, Wither J, Harley JB, Blanco I, et al. Relationship between genetic risk and age of diagnosis of systemic lupus erythematosus. J Rheumatol. 2020. https://doi.org/10.3899/jrheum.200002.
Chen L, Morris DL, Vyse TJ. Genetic advances in systemic lupus erythematosus. Curr Opin Rheumatol. 2017;29:423–33.
Webber D, Cao J, Dominguez D, Gladman DD, Levy DM, Ng L, et al. Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE. Rheumatology. 2020;59:90–8. https://doi.org/10.1093/rheumatology/kez220.
Liphaus BL, Caramalho I, Rangel-Santos A, Silva CA, Demengeot J, Carneiro-Sampaio MMS. LRBA deficiency: A new genetic cause of monogenic lupus. Ann Rheum Dis. 2019. https://doi.org/10.1136/annrheumdis-2019-216410.
Demirkaya E, Sahin S, Romano M, Zhou Q, Aksentijevich I. New horizons in the genetic etiology of systemic lupus erythematosus and lupus-like disease: monogenic lupus and beyond. J Clin Med. 2020;9:712. https://doi.org/10.3390/jcm9030712.
Costa-Reis P, Sullivan KE. Monogenic lupus: it’s all new! Curr Opin Immunol. 2017;49:87–95. https://doi.org/10.1016/j.coi.2017.10.008.
Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40:66–81.
Alperin JM, Ortiz-Fernández L, Sawalha AH. Monogenic lupus: a developing paradigm of disease. Front Immunol. 2018;9:2496. https://doi.org/10.3389/fimmu.2018.02496.
Carneiro-Sampaio M, Coutinho A. Early-onset autoimmune disease as a manifestation of primary immunodeficiency. Front Immunol. 2015. https://doi.org/10.3389/fimmu.2015.00185.
Rivas-Larrauri F, Yamazaki-Nakashimada MA. Lupus eritematoso sistémico: ¿es una sola enfermedad? Reumatol Clin. 2016;12:274–81. https://doi.org/10.1016/j.reuma.2016.01.005.
Figgett WA, Monaghan K, Ng M, Alhamdoosh M, Maraskovsky E, Wilson NJ, et al. Machine learning applied to whole-blood RNA-sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus. Clin Transl Immunol. 2019. https://doi.org/10.1002/cti2.1093.
Massias JS, Smith EMD, Al-Abadi E, Armon K, Bailey K, Ciurtin C, et al. Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups. Lupus. 2020;29:474–81. https://doi.org/10.1177/0961203320909156.
Rubinstein TB, Mowrey WB, Ilowite NT, Wahezi DM, Abramson L, Anderson E, et al. Delays to care in pediatric lupus patients: data from the childhood arthritis and rheumatology research alliance legacy registry. Arthritis Care Res. 2018;70:420–7. https://doi.org/10.1002/acr.23285.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. https://doi.org/10.1002/art.1780400928.
Petri M, Orbai AM, Alarcõn GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677–86. https://doi.org/10.1002/art.34473.
Lythgoe H, Morgan T, Heaf E, Lloyd O, Al-Abadi E, Armon K, et al. Evaluation of the ACR and SLICC classification criteria in juvenile-onset systemic lupus erythematosus: a longitudinal analysis. Lupus. 2017;26:1285–90. https://doi.org/10.1177/0961203317700484.
Tao JJ, Hiraki LT, Levy DM, Silverman ED. Comparison of sensitivities of American college of rheumatology and systemic lupus international collaborating clinics classification criteria in childhood-onset systemic lupus erythematosus. J Rheumatol. 2019;46:731–8. https://doi.org/10.3899/jrheum.180337.
Sag E, Tartaglione A, Batu ED, Ravelli A, Khalil SMA, Marks SD, et al. Performance of the new SLICC classification criteria in childhood systemic lupus erythematosus: a multicentre study. Clin Exp Rheumatol. 2014;32:440–4.
Fonseca AR, Gaspar-Elsas MIC, Land MGP, De Oliveira SKF. Comparison between three systems of classification criteria in juvenile systemic lupus erythematous. Rheumatology. 2015;54:241–7. https://doi.org/10.1093/rheumatology/keu278.
Hartman EAR, van Royen-Kerkhof A, Jacobs JWG, Welsing PMJ, Fritsch-Stork RDE. Performance of the 2012 Systemic Lupus International Collaborating Clinics classification criteria versus the 1997 American College of Rheumatology classification criteria in adult and juvenile systemic lupus erythematosus. A systematic review and meta-analysis. Autoimmun Rev. 2018;17:316–22. https://doi.org/10.1016/j.autrev.2018.01.007.
Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78:1151–9. https://doi.org/10.1136/annrheumdis-2018-214819.
Aljaberi N, Nguyen K, Strahle C, Merritt A, Mathur A, Brunner HI. The Performance of the New 2019-EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus in Children and Young Adults. Arthritis Care Res. 2020. https://doi.org/10.1002/acr.24430.
Ma M, Hui-Yuen JS, Cerise JE, Iqbal S, Eberhard BA. Validation of the 2019 European League Against Rheumatism/American College of Rheumatology Criteria Compared to the 1997 American College of Rheumatology Criteria and the 2012 Systemic Lupus International Collaborating Clinics Criteria in Pediatric Systemic Lupus Erythematosus. Arthritis Care Res. 2020;72:1597–601. https://doi.org/10.1002/acr.24057.
Fonseca AR, Rodrigues MCF, Sztajnbok FR, Land MGP, De Oliveira SKF. Comparison among ACR1997, SLICC and the new EULAR/ACR classification criteria in childhood-onset systemic lupus erythematosus. Adv Rheumatol. 2019. https://doi.org/10.1186/s42358-019-0062-z.
Lattanzi B, Consolaro A, Solari N, Ruperto N, Martini A, Ravelli A. Measures of disease activity and damage in pediatric systemic lupus erythematosus: British Isles Lupus Assessment Group (BILAG), European Consensus Lupus Activity Measurement (ECLAM), Systemic Lupus Activity Measure (SLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Physician’s Global Assessment of Disease Activity (MD Global), and Systemic Lupus International Collaborating. Arthritis Care Res. 2011;63(SUPPL):11. https://doi.org/10.1002/acr.20623.
Guariento A, Silva MFC, Tassetano PSF, Rocha SMS, Campos LMA, Valente M, et al. Biometria do fígado e do baço em pacientes com lúpus eritematoso sistêmico de início pediátrico. Rev Bras Reumatol. 2015;55:346–51. https://doi.org/10.1016/j.rbr.2014.12.010.
Groot N, De Graeff N, Avcin T, Bader-Meunier B, Brogan P, Dolezalova P, et al. European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupus erythematosus: The SHARE initiative. Ann Rheum Dis. 2017;76:1788–96. https://doi.org/10.1136/annrheumdis-2016-210960.
Groot N, De Graeff N, Marks SD, Brogan P, Avcin T, Bader-Meunier B, et al. European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: The SHARE initiative. Ann Rheum Dis. 2017;76:1965–73. https://doi.org/10.1136/annrheumdis-2017-211898.
Franklyn K, Lau CS, Navarra SV, Louthrenoo W, Lateef A, Hamijoyo L, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis. 2016;75:1615–21.
Golder V, Tsang-A-Sjoe MWP. Treatment targets in SLE: Remission and low disease activity state. Rheumatology. 2020;59:V19-28.
Golder V, Kandane-Rathnayake R, Huq M, Nim HT, Louthrenoo W, Luo SF, et al. Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. Lancet Rheumatol. 2019;1:e95-102. https://doi.org/10.1016/S2665-9913(19)30037-2.
Brunner HI, Holland M, Beresford MW, Ardoin SP, Appenzeller S, Silva CA, et al. American College of Rheumatology Provisional Criteria for global flares in childhood-onset systemic lupus erythematosus. Arthritis Care Res. 2018;70:813–22. https://doi.org/10.1002/acr.23557.
Brunner HI, Holland MJ, Beresford MW, Ardoin SP, Appenzeller S, Silva CA, et al. American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus. Arthritis Care Res. 2019;71:579–90. https://doi.org/10.1002/acr.23834.
Gutiérrez-Suárez R, Ruperto N, Gastaldi R, Pistorio A, Felici E, Burgos-Vargas 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;54:2989–96. https://doi.org/10.1002/art.22048.
Watson L, Leone V, Pilkington C, Tullus K, Rangaraj S, McDonagh JE, et al. Disease activity, severity, and damage in the UK Juvenile-onset systemic lupus erythematosus cohort. Arthritis Rheum. 2012;64:2356–65. https://doi.org/10.1002/art.34410.
Lim LSH, Lefebvre A, Benseler S, Silverman ED. Longterm outcomes and damage accrual in patients with childhood systemic lupus erythematosus with psychosis and severe cognitive dysfunction. J Rheumatol. 2013;40:513–9. https://doi.org/10.3899/jrheum.121096.
Holland MJ, Beresford MW, Feldman BM, Huggins J, Norambuena X, Silva CA, et al. Measuring disease damage and its severity in childhood-onset systemic lupus erythematosus. Arthritis Care Res. 2018;70:1621–9. https://doi.org/10.1002/acr.23531.
Salah S, Lotfy HM, Mokbel AN, Kaddah AM, Fahmy N. Damage index in childhood-onset systemic lupus erythematosus in Egypt. Pediatr Rheumatol. 2011. https://doi.org/10.1186/1546-0096-9-36.
Lim LSH, Pullenayegum E, Lim L, Gladman D, Feldman B, Silverman E. From childhood to adulthood: the trajectory of damage in patients with juvenile-onset systemic lupus erythematosus. Arthritis Care Res. 2017;69:1627–35. https://doi.org/10.1002/acr.23199.
Groot N, Shaikhani D, Teng YKO, de Leeuw K, Bijl M, Dolhain RJEM, et al. Long-term clinical outcomes in a cohort of adults with childhood-onset systemic lupus erythematosus. Arthritis Rheumatol. 2019;71:290–301. https://doi.org/10.1002/art.40697.
Pons-Estel GJ, Ugarte-Gil MF, Alarcón GS. Epidemiology of systemic lupus erythematosus. Expert Rev Clin Immunol. 2017;13:799–814. https://doi.org/10.1080/1744666X.2017.1327352.
Brunner HI, Martini A, Lovell DJ, Ruperto N. Clinical trials in children and adolescents with systemic lupus erythematosus: Methodological aspects, regulatory landscape and future opportunities. Ann Rheum Dis. 2019;78:162–70. https://doi.org/10.1136/annrheumdis-2018-213198.
Rubin HR, Pronovost P, Diette GB. The advantages and disadvantages of process-based measures of health care quality. Int J Qual Heal Care. 2001;13:469–74. https://doi.org/10.1093/intqhc/13.6.469.
Hollander MC, Sage JM, Greenler AJ, Pendl J, Avcin T, Espada G, et al. International consensus for provisions of quality-driven care in childhood-onset systemic lupus erythematosus. Arthritis Care Res. 2013;65:1416–23.
Mina R, Harris JG, Klein-Gitelman MS, Appenzeller S, Centeville M, Eskra D, et al. Initial benchmarking of the quality of medical care in childhood-onset systemic lupus erythematosus. Arthritis Care Res. 2016;68:179–86.
Silva CA, Aikawa NE, Bonfa E. Vaccinations in juvenile chronic inflammatory diseases: an update. Nat Rev Rheumatol. 2013;9:532–43.
Rotstein Grein IH, Pinto NF, Lobo A, Groot N, Sztajnbok F, da Silva CAA, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in patients with childhood systemic lupus erythematosus: a real-world interventional multi-centre study. Lupus. 2020;29:934–42.
Groot N, Heijstek MW, Wulffraat NM. Vaccinations in paediatric rheumatology: an update on current developments. Curr Rheumatol Rep. 2015;17:46.
Schulze-Koops H, Specker C, Skapenko A. Vaccination of patients with inflammatory rheumatic diseases against SARS-CoV-2: considerations before widespread availability of the vaccines. RMD Open. 2021;7(1):e001553. https://doi.org/10.1136/rmdopen-2020-001553
Tang W, Askanase AD, Khalili L, Merrill JT. SARS-CoV-2 vaccines in patients with SLE. Lupus Sci Med. 2021;8(1):e000479.https://doi.org/10.1136/lupus-2021-000479
Wallace M, Woodworth KR, Gargano JW, Scobie HM, Blain AE, Moulia D, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine in Adolescents Aged 12–15 Years—United States, May 2021. MMWR Morb Mortal Wkly Rep. 2021;70:749–52. https://doi.org/10.15585/mmwr.mm7020e1.
Kelvin AA, Halperin S. COVID-19 in children: the link in the transmission chain. Lancet Infect Dis. 2020;20:633–4.
Wang E, Brar K. COVID-19 in Children: an epidemiology study from China. J Allergy Clin Immunol Pract. 2020;8:2118–20.
Avar Aydin PO, Shan J, Brunner HI, Mitsnefes MM. Blood pressure control over time in childhood-onset systemic lupus erythematous. Lupus. 2018;27:657–64. https://doi.org/10.1177/0961203317751061.
Fanouriakis A, Kostopoulou M, Cheema K, Anders HJ, Aringer M, Bajema I, et al. 2019 Update of the Joint European League against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020;79:S713–23. https://doi.org/10.1136/annrheumdis-2020-216924.
Ugolini-Lopes MR, Seguro LPC, Castro MXF, Daffre D, Lopes AC, Borba EF, et al. Early proteinuria response: a valid real-life situation predictor of long-term lupus renal outcome in an ethnically diverse group with severe biopsy-proven nephritis? Lupus Sci Med. 2017. https://doi.org/10.1136/lupus-2017-000213.
Castro M, Ugolini-Lopes M, Borba EF, Bonfá E, Seguro LPC. Effectiveness of renoprotective approaches for persistent proteinuria in lupus nephritis: more than just immunosuppression. Lupus. 2018;27:2215–9.
Klumb EM, Silva CAA, Lanna CCD, Sato EI, Borba EF, Brenol JCT, et al. Consenso da Sociedade Brasileira de Reumatologia para o diagnóstico, manejo e tratamento da nefrite lúpica. Rev Bras Reumatol. 2015;55:1–21.
Gordon C, Amissah-Arthur MB, Gayed M, Brown S, Bruce IN, D’Cruz D, et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology (Oxford). 2018;57:e1-45.
Gualano B, Bonfa E, Pereira RMR, Silva CA. Physical activity for paediatric rheumatic diseases: standing up against old paradigms. Nat Rev Rheumatol. 2017;13:368–79. https://doi.org/10.1038/nrrheum.2017.75.
Pinto AJ, Miyake CNH, Benatti FB, Silva CA, Sallum AME, Borba E, et al. Reduced aerobic capacity and quality of life in physically inactive patients with systemic lupus erythematosus with mild or inactive disease. Arthritis Care Res. 2016;68:1780–6. https://doi.org/10.1002/acr.22905.
Putera AM, Irwanto I, Maramis MM, Prasetyo RV, Soemyarso NA, Noer MS. Effect of mental health problems on the quality of life in children with lupus nephritis. Neuropsychiatr Dis Treat. 2020;16:1583–93.
Knight AM, Vickery ME, Muscal E, Davis AM, Harris JG, Soybilgic A, et al. Identifying targets for improving mental healthcare of adolescents with systemic lupus erythematosus: perspectives from pediatric rheumatology clinicians in the United States and Canada. J Rheumatol. 2016;43:1136–45.
Jones JT, Cunningham N, Kashikar-Zuck S, Brunner HI. Pain, fatigue, and psychological impact on health-related quality of life in childhood-onset lupus. Arthritis Care Res. 2016;68:73–80. https://doi.org/10.1002/acr.22650.
Rodriguez-Smith J, Brunner HI. Update on the treatment and outcome of systemic lupus erythematous in children. Curr Opin Rheumatol. 2019;31:464–70. https://doi.org/10.1097/BOR.0000000000000621.
Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf. 2017;16:411–9. https://doi.org/10.1080/14740338.2017.1269168.
Harris JG, Maletta KI, Kuhn EM, Olson JC. Evaluation of quality indicators and disease damage in childhood-onset systemic lupus erythematosus patients. Clin Rheumatol. 2017;36:351–9. https://doi.org/10.1007/s10067-016-3518-0.
Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, Lum F. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123:1386–94. https://doi.org/10.1016/j.ophtha.2016.01.058.
Deng J, Chalhoub NE, Sherwin CM, Li C, Brunner HI. Glucocorticoids pharmacology and their application in the treatment of childhood-onset systemic lupus erythematosus. Semin Arthritis Rheum. 2019;49:251–9. https://doi.org/10.1016/j.semarthrit.2019.03.010.
Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T, et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature. 2010;465:937–41.
Heshin-Bekenstein M, Trupin L, Yelin E, von Scheven E, Yazdany J, Lawson EF. Longitudinal disease- and steroid-related damage among adults with childhood-onset systemic lupus erythematosus. Semin Arthritis Rheum. 2019;49:267–72. https://doi.org/10.1016/j.semarthrit.2019.05.010.
Sawah S Al, Zhang X, Zhu B, Magder LS, Foster SA, Iikuni N, et al. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus-the Hopkins Lupus Cohort. Lupus Sci Med. 2015;2:66. https://doi.org/10.1136/lupus-2014-000066.
Dye AM, Nelson GB, Diaz-Thomas A. Delayed puberty. Pediatr Ann. 2018;47:e16-22. https://doi.org/10.3928/19382359-20171215-01.
Jongvilaikasem P, Rianthavorn P. Longitudinal growth patterns and final height in childhood-onset systemic lupus erythematosus. Eur J Pediatr. 2021;180:1431–41. https://doi.org/10.1007/s00431-020-03910-2.
Rygg M, Pistorio A, Ravelli A, Maghnie M, Di IN, Bader-Meunier B, et al. A longitudinal PRINTO study on growth and puberty in juvenile systemic lupus erythematosus. Ann Rheum Dis. 2012;71:511–7. https://doi.org/10.1136/annrheumdis-2011-200106.
Peterknecht E, Keasey MP, Beresford MW. The effectiveness and safety of biological therapeutics in juvenile-onset systemic lupus erythematosus (JSLE): a systematic review. Lupus. 2018;27:2135–45. https://doi.org/10.1177/0961203318804879.
Neely J, von Scheven E. Autoimmune haemolytic anaemia and autoimmune thrombocytopenia in childhood-onset systemic lupus erythematosus: updates on pathogenesis and treatment. Curr Opin Rheumatol. 2018;30:498–505. https://doi.org/10.1097/BOR.0000000000000523.
Correll CK, Miller DD, Maguiness SM. Treatment of Childhood-Onset Lupus Erythematosus Panniculitis with Rituximab. JAMA Dermatol. 2020;156:566–9. https://doi.org/10.1001/jamadermatol.2019.4984.
AlE’ed A, AlSonbul A, Al-Mayouf SM. Safety and efficacy of combined cyclophosphamide and rituximab treatment in recalcitrant childhood lupus. Rheumatol Int. 2014;34:529–33.
Speth F, Hinze CH, Schranz P, Miller-Wiegart E, Haefner R. Combination of rituximab and abatacept as an exit strategy for repetitive B-cell depletion in children with severe autoimmune diseases: a report of three cases. Lupus. 2018;27:1996–8. https://doi.org/10.1177/0961203318783057.
Yu T, Enioutina EY, Brunner HI, Vinks AA, Sherwin CM. Clinical pharmacokinetics and pharmacodynamics of biologic therapeutics for treatment of systemic lupus erythematosus. Clin Pharmacokinet. 2017;56:107–25. https://doi.org/10.1007/s40262-016-0426-z.
Brunner HI, Abud-Mendoza C, Viola DO, Calvo Penades I, Levy D, Anton J, et al. Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial. Ann Rheum Dis. 2020;79:1340–8. https://doi.org/10.1136/annrheumdis-2020-217101.
Shah K, Cragg M, Leandro M, Reddy V. Anti-CD20 monoclonal antibodies in systemic lupus erythematosus. Biologicals. 2021;69:1–14.
Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:1909–16.
Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti–interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017;69:376–86.
Tocut M, Shoenfeld Y, Zandman-Goddard G. Systemic lupus erythematosus: an expert insight into emerging therapy agents in preclinical and early clinical development. Expert Opin Investig Drugs. 2020;29:1151–62.
Cinar OK, Marlais M, Al Obaidi M, Cheng IL, Tullus K, Brogan P, et al. Ofatumumab use in juvenile systemic lupus erythematosus: a single centre experience. Lupus. 2021;30:527–30.
Pin A, Tesser A, Pastore S, Moressa V, Valencic E, Arbo A, et al. Biological and clinical changes in a pediatric series treated with off-label JAK inhibitors. Int J Mol Sci. 2020;21:1–29.
Mok CC. Calcineurin inhibitors in systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2017;31:429–38. https://doi.org/10.1016/j.berh.2017.09.010.
Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. 2015;162:18–26.
Rovin BH, Solomons N, Pendergraft WF, Dooley MA, Tumlin J, Romero-Diaz J, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. 2019;95:219–31.
Palmer SC, Tunnicliffe DJ, Singh-Grewal D, Mavridis D, Tonelli M, Johnson DW, et al. Induction and maintenance immunosuppression treatment of proliferative lupus nephritis: a network meta-analysis of randomized trials. Am J Kidney Dis. 2017;70:324–36.
Mok CC, Ying KY, Yim CW, Siu YP, Tong KH, To CH, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis. 2016;75:30–6.
Tiseo BC, Cocuzza M, Bonfá E, Srougi M, Silva CA. Male fertility potential alteration in rheumatic diseases: a systematic review. Int Braz J Urol. 2016;42:11–21.
Parodis I, Tamirou F, Houssiau FA. Prediction of prognosis and renal outcome in lupus nephritis. Lupus Sci Med. 2020. https://doi.org/10.1136/lupus-2020-000389.
Wenderfer SE, Ruth NM, Brunner HI. Advances in the care of children with lupus nephritis. Pediatr Res. 2017;81:406–14. https://doi.org/10.1038/pr.2016.247.
Dall’Era M, Cisternas MG, Smilek DE, Straub L, Houssiau FA, Cervera R, et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the euro-lupus nephritis cohort. Arthritis Rheumatol. 2015;67:1305–13. https://doi.org/10.1002/art.39026.
Tamirou F, Lauwerys BR, Dall’Era M, Mackay M, Rovin B, Cervera R, et al. A proteinuria cut-off level of 0.7 g /day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: Data from the MAINTAIN Nephritis Trial. Lupus Sci Med. 2015. https://doi.org/10.1136/lupus-2015-000123.
Mackay M, Dall’Era M, Fishbein J, Kalunian K, Lesser M, Sanchez-Guerrero J, et al. Establishing surrogate kidney end points for lupus nephritis clinical trials: development and validation of a novel approach to predict future kidney outcomes. Arthritis Rheumatol. 2019;71:411–9. https://doi.org/10.1002/art.40724.
Baqi N, Moazami S, Singh A, Ahmad H, Balachandra S, Tejani A. Lupus nephritis in children: a longitudinal study of prognostic factors and therapy. J Am Soc Nephrol. 1996;7:924–9.
Mahajan A, Amelio J, Gairy K, Kaur G, Levy RA, Roth D, et al. Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping disease severity and progression. Lupus. 2020;29:1011–20. https://doi.org/10.1177/0961203320932219.
Kavanaugh AF, Solomon DH, Schur P, Reveille JD, Sherrer YRS, Lahita R. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests. Arthritis Care Res. 2002;47:546–55. https://doi.org/10.1002/art.10558.
Watson L, Tullus K, Pilkington C, Chesters C, Marks SD, Newland P, et al. Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study. Pediatr Nephrol. 2014;29:397–405. https://doi.org/10.1007/s00467-013-2668-4.
Brunner HI, Gulati G, Klein-Gitelman MS, Rouster-Stevens KA, Tucker L, Ardoin SP, et al. Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus. Pediatr Nephrol. 2019;34:117–28. https://doi.org/10.1007/s00467-018-4049-5.
Harry O, Crosby LE, Smith AW, Favier L, Aljaberi N, Ting TV, et al. Self-management and adherence in childhood-onset systemic lupus erythematosus: what are we missing? Lupus. 2019;28:642–50. https://doi.org/10.1177/0961203319839478.
van Weelden M, Queiroz LB, Lourenço DMR, Kozua K, Lourenço B, Silva CA. Alcohol, smoking and illicit drug use in pediatric systemic lupus erythematosus patients. Rev Bras Reumatol. 2016;56:228–34. https://doi.org/10.1016/j.rbre.2016.02.001.
Tunnicliffe DJ, Singh-Grewal D, Chaitow J, MacKie F, Manolios N, Lin MW, et al. Lupus means sacrifices: perspectives of adolescents and young adults with systemic lupus erythematosus. Arthritis Care Res. 2016;68:828–37. https://doi.org/10.1002/acr.22749.
Davis AM, Graham TB, Zhu Y, McPheeters ML. Depression and medication nonadherence in childhood-onset systemic lupus erythematosus. Lupus. 2018;27:1532–41. https://doi.org/10.1177/0961203318779710.
Bugni VM, Ozaki LS, Okamoto KYK, Barbosa CMPL, Hilário MOE, Len CA, et al. Factors associated with adherence to treatment in children and adolescents with chronic rheumatic diseases. J Pediatr (Rio J). 2012;88:483–8. https://doi.org/10.2223/JPED.2227.
Oliveira-Santos M, Verani JFS, Klumb EM, Albuquerque EMN. Evaluation of adherence to drug treatment in patients with systemic lupus erythematosus in Brazil. Lupus. 2011;20:320–9. https://doi.org/10.1177/0961203310383736.
Feldman CH, Yazdany J, Guan H, Solomon DH, Costenbader KH. Medication nonadherence is associated with increased subsequent acute care utilization among medicaid beneficiaries with systemic lupus erythematosus. Arthritis Care Res. 2015;67:1712–21. https://doi.org/10.1002/acr.22636.
Miotto e Silva VB, Okamoto KYK, Da Silva Ozaki L, Len CA, Sande e Lemos Ramos Ascensão Terreri MT de. Early detection of poor adherence to treatment of pediatric rheumatic diseases: pediatric rheumatology adherence questionnaire—a pilot study. Rev Paul Pediatr. 2019;37:149–55. https://doi.org/10.1590/1984-0462/;2019;37;2;00015.
Scalzi LV, Hollenbeak CS, Mascuilli E, Olsen N. Improvement of medication adherence in adolescents and young adults with SLE using web-based education with and without a social media intervention, a pilot study. Pediatr Rheumatol. 2018;16:18. https://doi.org/10.1186/s12969-018-0232-2.
Dantas LO, Weber S, Osani MC, Bannuru RR, McAlindon TE, Kasturi S. Mobile health technologies for the management of systemic lupus erythematosus: a systematic review. Lupus. 2020;29:144–56. https://doi.org/10.1177/0961203319897139.
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Our study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 305798/2020-0 to M-CS, 305242/2019-9 to EB and 304984/2020-5 to CAS), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2015/03756-4 to EB and CAS) and by Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to MCS and CAS.
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Trindade, V.C., Carneiro-Sampaio, M., Bonfa, E. et al. An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus. Pediatr Drugs 23, 331–347 (2021). https://doi.org/10.1007/s40272-021-00457-z
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DOI: https://doi.org/10.1007/s40272-021-00457-z