Update Management of SLE Vitor

Pediatric Drugs (2021) 23:331–347
https://doi.org/10.1007/s40272-021-00457-z
LEADING ARTICLE
An Update on the Management of Childhood‑Onset Systemic Lupus

Erythematosus
Vitor Cavalcanti Trindade1 · Magda Carneiro‑Sampaio1 · Eloisa Bonfa2 · Clovis Artur Silva1,2
Accepted: 9 June 2021 / Published online: 10 July 2021

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021
Abstract
Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a multisystemic, inflammatory, heterogeneous auto-
immune condition. This disease is characterized by simultaneous or sequential organ and system involvement, with unpredict-
able 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 stud-
ies, 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 recom-
mended 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 inflamma-
tory 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.
1 Introduction involvement, with unpredictable flare and high morbimor-

tality [1–24].
Childhood-onset systemic lupus erythematosus (cSLE) is cSLE presentation and severity may vary according to
a prototype of a multisystemic, inflammatory, heterogene- genetic background and socioeconomic status [14]. This
ous autoimmune condition. This chronic condition is char- condition may be associated with irreversible accrual of
acterized by simultaneous or sequential organ and system damage, reduced health-related quality of life, and dimin-
ished life expectancy, mainly due to infections and recur-
rence of disease activity [18, 19].
* Clovis Artur Silva
clovis.silva@hc.fm.usp.br The hallmark of cSLE is the wide spectrum of clinical
and laboratory abnormalities, particularly with the produc-
1
Children and Adolescent Institute, Faculdade de Medicina, tion of multiple autoantibodies against histone, nonhistone,
Hospital das Clinicas HCFMUSP, Universidade de São cytoplasm, and nuclear proteins, and a marked increase in
Paulo, São Paulo, Brazil
proinflammatory cytokines [11, 12, 14–16]. The clinical
2
Rheumatology Division, Faculdade de Medicina, Hospital cSLE presentation spectrum is very diverse, varying from
das Clinicas HCFMUSP, Universidade de São Paulo,
Av. Dr. Enéas Carvalho de Aguiar, 647, Cerqueira César, acute, severe, life-threatening disease to chronic condition
São Paulo, SP 05403‑000, Brazil with an intermittent or continuous course, and is rarely
Vol.:(0123456789)
332 V. C. Trindade et al.
2 Pathogenesis
Key Points
Multiple immunologic abnormalities that occur in SLE
Belimumab, a monoclonal antibody that blocks the bind- patients are molecular targets for treatment. cSLE pathogen-
ing of soluble B lymphocyte stimulator to B cells, was esis is a combination of inherited susceptibility, gestational
recently approved by the US Food and Drug Administra- and perinatal-related factors, hormonal changes, and envi-
tion for childhood-onset systemic lupus erythematosus ronmental exposures, such as sunlight, drugs, viral infec-
(cSLE) treatment in children aged >5 years. tions, and air pollutants (carbon monoxide, sulfur dioxide,
Calcineurin inhibitors (cyclosporine, tacrolimus, voclo- nitrogen dioxide, ozone, and particulate matter) [2, 38–41].
sporin) appear to be a good option for cSLE patients cSLE is also characterized by complex immune dys-
with lupus nephritis. regulation, involving both innate and adaptative immunity,
leading to a loss of self-tolerance followed by a sustained
Anti-interferon therapies (sifalimumab and anifrolumab) production of pathogenic autoantibodies targeting nuclear
have shown beneficial results in adult SLE patients, as antigens [42, 43].
have Janus kinase inhibitors, and could in the future be The innate immune system is responsible for a non-
an alternative treatment for pediatric patients with severe specific inflammatory response to pathogens. It includes
interferon-mediated inflammatory disease. a range of cells and soluble factors, such as antigen-pre-
New therapies targeting CD20, such as atacicept and senting cells (APC), cytokines, and complement proteins.
telitacicept, seem to be other promising drugs for SLE Dendritic cells are the main APC, and a subgroup, the
patients. 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
associated with spontaneous remission without treatment [45]. Podocytes in cSLE patients with active nephritis
[1, 2, 11]. express TLR9 and this was related to proteinuria and
A more aggressive course and disease flares associated increased anti-dsDNA antibody [46]. Antimalarial drugs
with higher morbidity and mortality rates have been reported modulate the TLR7 and TLR9 signaling [47].
at diagnosis and follow-up in cSLE patients compared with Importantly, the IFN-α signature is a central player
adult-onset SLE. Indeed, cSLE patients had a higher preva- in SLE pathogenesis [48–52]. IFN-α is elevated in SLE
lence of initial and cumulative multiorgan system involve- patients, particularly during disease flares, and this
ment, such as nephritis, neuropsychiatric, hematological, cytokine was increased in cSLE patients compared with
and macrophage activation syndrome, than adult-onset their first-degree relatives and healthy controls, even
SLE patients [13, 25–35]. In contrast, late-onset SLE (> 50 in patients receiving medication [51]. IFN drives the
years) patients had the lowest prevalence of constitutional inflammation in SLE and activates different cell types
and mucocutaneous manifestations, serositis, and hypocom- in the immune system, contributing to immunological
plementemia compared with cSLE and adult-onset SLE [36]. dysregulation [53–55]. IFN-I also augments APC func-
Children and adolescent patients use the same immunosup- tion and promotes apoptosis [48]. The IFN-I signature
pressive agents as adult SLE patients, and generally require occurred in approximately 60% of cSLE patients and
more aggressive treatment to achieve disease control than was associated with increased TLR7 expression of cyto-
adult SLE populations [1, 2, 25, 28–31]. solic nucleic acid binding receptors [56]. Associations
Most treatments in cSLE and adult-onset SLE are off- were also reported between IFN-I and several markers
label drugs with recommendations based on inadequately of immune activation, such as complement, and autoan-
powered studies, therapeutic consensus guidelines, or case tibody production, such dsDNA antibodies, which start
series [1, 2, 13, 18, 19]. Racial/ethnic background, cost of and may also maintain SLE disease activity over time
medications, poor adherence, and specifically social deter- [51, 57]. Interestingly, there are now targeted thera-
minants of health seem to impact lupus outcomes and treat- pies that can potentially modify this IFN signature (see
ment response [18, 19, 37]. Sect. 5).
The objective of this narrative review is to provide an Increased apoptosis [32, 42] and impaired clearance
update of recent new findings relevant to the manage- of apoptotic debris allow the presentation of nucleic
ment of cSLE, particularly focusing on pharmacological acid self-antigens and perpetuate inflammation in cSLE
therapy. [58]. The complement system is also relevant in the
An Update on the Management of Childhood-Onset 333
degradation and removal of chromatin produced during 3 Childhood‑Onset Systemic Lupus

cell death [20, 59–62]. The loss of tolerance to self-anti- Erythematosus (cSLE) Stratification
gens in SLE can also be induced by lymphocyte abnor- and New Validated Classification Criteria
malities. T-cell functional and phenotypic alterations
have implications in SLE pathogenesis [63]. The failure Lupus is a very heterogeneous disease and the response to
of T cells to produce IL-2 leads to a reduction in regula- treatment is very difficult to predict. This heterogeneity is
tory T cells and increased effector T cells, especially the one of the reasons for the high failure rate of target therapy
T helper 17 (Th17) phenotype. This imbalance contrib- trials. Stratification schemes and accurate classification cri-
utes to a pro-inflammatory status in adult-onset SLE and teria of cSLE patients represent potential ways of refining
cSLE [64–66]. Additionally, changes in T-cell receptors cSLE clinical trials [80].
observed in SLE result in hyperactivation of their signal- Studies evaluating cSLE stratification at disease onset and
ing pathway [64, 67]. Azathioprine and mycophenolate during the disease course have been reported to differentiate
mofetil are immunosuppressive agents that can interfere clinical and laboratory abnormalities according to age and
with T-cell function. Autoantibody production is a hall- diagnostic delay [20–22, 81, 82].
mark of lupus, and B-cell defects can account for this. A large, retrospective, multicenter cohort study in Bra-
B lymphocyte stimulator (BLyS) levels are elevated in zil assessed demographic data, clinical manifestations, and
cSLE [68] and contribute to a breakdown in self-tol- laboratory exams at disease diagnosis in three age groups
erance. Biological agents, such as rituximab and beli- of cSLE: early-onset (< 6 years), school-age (≥ 6 and <
mumab, are B-cell pathway-targeting therapy for cSLE. 12 years), and adolescent (≥ 12 and < 18 years). Fever,
Another relevant factor in cSLE pathogenesis is genetic hepatomegaly, and splenomegaly occurred more often in
background, supported by 10-fold increased concordance in the early-onset group, and weight loss, photosensitivity,
monozygotic compared with dizygotic twins [69]. A recent and leukopenia/lymphopenia in the adolescent group [20].
genomic DNA study including 2001 multi-ethnic SLE Similarly, a British cohort assessed cSLE patients based on
patients demonstrated an inverse association between age age at disease presentation: pre-pubertal (< 7 years), peri-
and genetic risk score involving genes outside of the HLA pubertal (8–13 years), and adolescent groups (14–18 years).
complex [70]. cSLE is usually a polygenic disease and more The adolescents had lower levels of white cell count, and
than 80 different genes in genome-wide association studies higher frequencies of disease activity, low complement lev-
were associated with SLE [71], mainly affecting multiple els, antinuclear antibodies (ANA) positive, and anti-dsDNA
pathways of the immune system [42, 64, 72]. titers compared with the other groups [81]. Regarding the
Furthermore, single gene defects associated with cSLE accrual damage at the last follow-up, both the Brazilian and
are very rare [73], involving different immune pathogenetic British cSLE groups demonstrated that disease damage
pathways, such as the complement system, phagocyte oxi- scores were comparable between the age groups [22, 81].
dase system, apoptosis, nucleic acid repair, DNA degrada- The Brazilian registry assessed 1533 cSLE patients based
tion, DNA sensing, type I IFN, and B-cell development on three groups with different periods between the onset of
[74, 75]. Inborn errors of immunity are caused by mono- signs/symptoms and the diagnosis. This study revealed cSLE
genic mutations, resulting in loss or gain of function of the patients infrequently had a shorter time interval to diagno-
encoded protein, and may present as increased susceptibility sis (< 1 month) characterized by multisystemic, severe, and
to infectious diseases, allergic, malignant, autoinflammatory active conditions, whereas the majority of cSLE patients had
and autoimmune conditions [76]. a long-time interval (≥ 3 months) to diagnosis, with mild
Genetic analysis to assess monogenic lupus (whole disease onset [21].
exome or whole genome sequencing) is very impor- Three classification criteria have been proposed for SLE
tant to improve the knowledge of the genetic basis and patients to use in daily clinical practice, research, and clini-
increase options for new drug targets and biomarker cal trials [83, 84]. The American College of Rheumatology
development [77], and therefore should be considered classification criteria modified in 1997 (1997-ACR) are the
for cSLE patients with early onset of lupus manifesta- most universally used for cSLE patients [19, 83]. In 2012,
tions (mainly in infants and toddlers with cSLE) [78]. the Systemic Lupus International Collaborating Clinics
Patients with the gene defect have a specific disease (2012-SLICC) group published a new set of classification
presentation and progression [79], such as recurrent diagnostic criteria, including a stand-alone renal criterion for
infection and prominent cutaneous manifestation, cSLE patients with biopsy compatible with lupus nephritis
requiring personalized management. and positive ANA or anti-dsDNA antibodies [84].
Studies compared the performance of these two sets of There is a new description of low disease activity in SLE
criteria in pediatric lupus populations [85–88] and reported patients. The definition of lupus low disease activity state
a higher sensitivity for the 2012-SLICC criteria [85–88] (LLDAS) includes SLEDAI-2K ≤ 4, without any activ-
and higher specificity for the 1997-ACR criteria. A recent ity in major organ systems and no new features of activity
meta-analysis established that the 1997-ACR criteria had the compared with the previous evaluation, Safety of Estrogens
best overall performances for cSLE, even if associated with in Lupus Erythematosus National Assessment (SELENA)-
lower sensitivity [89]. In 2019, the European League Against SLEDAI physician global assessment ≤ 1; current predni-
Rheumatism (EULAR) and the ACR developed new classi- solone dose ≤ 7.5 mg/day and standard maintenance doses
fication criteria for systemic lupus preserving the specificity of immunosuppressants and approved biological drugs
of the 1997-ACR and the sensitivity of the SLICC criteria [98]. Importantly, this parameter has proven to be associ-
in adult SLE [90]. The 2019 EULAR/ACR classification ated with a decrease in SLE flares, reduced risk of disease
criteria proposed weighted criteria grouped in seven clini- damage, and may be used as a treat-to-target approach in
cal and three immunological domains, using ANA positive daily clinical practice and for future SLE clinical trials [99].
as a mandatory entry criterion. A score of ≥ 10 classifies a A prospective validation study with 1707 adult SLE patients
patient as SLE [90]. showed that the percentage of subjects with accrual damage
Three recent reports evaluated 2019-EULAR/ACR clas- was significantly lower in patients who achieved sustained
sification criteria in cSLE patients. The 2019-EULAR/ LLDAS compared with those that never experienced sus-
ACR criteria effectively classify cSLE, irrespective of tained LLDAS (2.9% vs 17.8%) [100]. Further prospective
age, sex, and race, and these new criteria were more sensi- multicenter studies will be necessary to assess LLDAS in
tive (85% vs 72%) with comparable specificity in youths cSLE populations.
with SLE compared with the 1997-ACR criteria (83% vs Recent provisional criteria for global flares in cSLE
87%) [91]. Another study showed the same sensitivity patients were also established after consensus formation
for 2019-EULAR/ACR and 2012-SLICC criteria (97.4%) methodology with pediatric rheumatologists and pediat-
and it was higher compared with the 1997-ACR criteria in ric nephrologists, and defined threshold levels for minor,
cSLE patients (87.2%), with similar specificity between moderate, and major flares. These criteria included the most
2012-SLICC and 2019-EULAR/ACR criteria (98.4% and important disease activity scores and inflammatory mark-
99.7%, respectively) [92]. Fonseca et al. showed that a 2019- ers, and they are therefore relevant for measuring systemic
EULAR/ACR total score ≥ 13 was more appropriate to clas- responses to interventions intended to treat systemic or
sify Brazilian cSLE patients than the proposed score of ≥ 10 organ-specific involvements of cSLE patients. One of these
and that 2012-SLICC criteria better scored for cSLE at the criteria was the SLEDAI-based algorithm (0.5 × ΔSLEDAI
first visit and 1-year-follow-up [93]. + 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,
4 Monitoring Disease Activity and Damage respectively. The other criterion was based on BILAG algo-
rithm (0.4 × ΔBILAG + 0.65 × Δprotein/creatinine ratio +
Disease activity evaluation includes different reliable and 0.5 × ΔMD-global + 0.02 × Δerythrocyte sedimentation
valid instruments for use in academic and clinical practice rate), and flare scores of ≥ 7.4/3.7/2.2 constituted major/
for cSLE [2, 94, 95]. The most important validated overall moderate/minor flares, respectively [101]. These criteria are
disease activity scores are Systemic Lupus Erythemato- relevant instruments for future use in clinical trials, allowing
sus Disease Activity Index (SLEDAI), British Isles Lupus longitudinal assessment of cSLE patients and measurement
Assessment Group (BILAG), and Medical Global Assess- of overall disease course since existing treatments used in
ment of Disease Activity (MD Global) [94]. cSLE are not uniformly effective in reducing disease activ-
Recently, European evidence-based recommendations for ity [101].
diagnosis and treatment of cSLE and childhood-onset lupus In addition, the same international consensus with pedi-
nephritis were established by consensus meetings [96, 97]. atric rheumatologists and nephrologists also established
One of these recommendations was that all cSLE patients a provisional index of clinically relevant improvement in
should have disease activity parameters evaluated regularly cSLE. This is an important instrument to assess response
in clinical practice, using one of the two standardized vali- to treatment and to classify the degree of improvement as
dated disease activity instruments: SLEDAI 2000 (SLEDAI- minor, moderate, or major [102].
2K) or pediatric BILAG index 2004 (pBILAG-2004) [96]. Systemic Lupus International Collaborating Clin-
Therefore, disease activity tools should be used at cSLE ics/American College of Rheumatology Damage Index
diagnosis and during the disease course. (SDI) score evaluates cumulative damage, indicating an
overall measurement of disease activity and severity in SLE immunosuppression are the main focus of pharmacologi-
patients. This score is validated for pediatric lupus patients cal management, and specific therapy should be individu-
and has been demonstrated to be a valid and reliable instru- alized according to the manifestations and severity of the
ment for cSLE [2]. It is a mainly disease-related outcome, disease. cSLE management requires a multidisciplinary and
while treatment with glucocorticoids, immunosuppressive multiprofessional team, led by a qualified pediatric rheu-
and biological agents are also risk factors for increased dam- matologist who can co-ordinate the patient’s support with
age score [2, 22]. all pediatric subspecialties [1, 2, 13]. Presently, there is a
A pediatric version of SDI is also available for clinical lack of high-quality evidence of multinational clinical trials,
practice in cSLE, including two additional domains: growth and therefore the majority of treatments have been adapted
failure and delay in secondary sexual characteristics [103]. from adult protocols and are mainly established by clinical
European evidence-based recommendations for diagnosis experience, clinical practice guidelines, and retrospective
and treatment of cSLE also suggested that patients with case series [2, 13, 66, 111].
cSLE should have cumulative damage assessed yearly using Health quality measures are tools used by care manage-
a standardized damage parameter, primarily using pediatric ment organizations to provide high-quality health care for
SDI [96]. patients [112]. International consensus recommendations for
The SDI instrument is the sum of SDI item scores. The care of cSLE patients included nine quality indicators: diag-
frequency of SDI score ≥ 1 ranged from 28% to 52% of nostic testing, education of cardiovascular risk and lifestyles,
cSLE populations, generally evidenced after 2–4 years of lupus nephritis, bone health, ophthalmologic examination,
diagnosis [104, 105]. A recent, international multicenter medical transition to adult clinic care, pregnancy, medica-
study including 1048 cSLE patients with a mean disease tion management, and immunization [113]. A further multi-
duration of 3.8 years evidenced that almost half the patients center and multinational study including 483 cSLE showed
had disease-related damage measured by SDI score. The that larger tertiary pediatric rheumatology centers tended
most frequently scored items were proteinuria, scarring alo- to meet these cSLE quality indicators and offer standards
pecia, and cognitive impairment [106]. Neuropsychiatric and of medical care more often than smaller centers. Notably,
renal involvements were the main predictors of higher dam- assessment of bone mineral density in patients exposed to
age accrual over time in another report [107]. glucocorticoids ranged widely among the centers involved
Two other prospective studies from Canada and the (7–90%), and some centers reported low accessibility to kid-
Netherland assessed the long-term outcomes of adult ney biopsies [114].
SLE patients with pediatric onset. A longitudinal damage
study with 473 SLE patients showed that baseline features, 5.1 General Treatment
Afro-Caribbean ethnicity, short diagnosis lag time, and the
presence of major organ and system involvements (lupus General management practices for cSLE patients include
nephritis class III/V, cerebrovascular accidents, vasculitis, sunscreen protection, a well-balanced diet with low salt and
alveolar hemorrhage, and/or myocarditis) were significantly adequate calcium consumption, and immunization against
associated with more damage [108]. Another study of 111 common pathogens [2]. Due to immune dysregulation and
cSLE patients with median disease duration of 20 years immunosuppressive treatment, cSLE patients have a marked
demonstrated that acute cerebrovascular accident, renal increased risk of infections. Indeed, infections are one of the
transplantation, replacement arthroplasties, and acute myo- most common causes of mortality and can induce a disease
cardial infarction were evidenced in the ages of 20 years, 24 flare in these patients [22]. Therefore, immunization is a
years, 34 years, and 39 years, respectively [109]. Since the powerful tool to reduce the burden of infectious diseases
mortality rate of SLE has progressively decreased in the last in the clinical management of cSLE and is recommended
decades [110], the prevention of organ damage is one of the to be undertaken prior to the initiation of immunosuppres-
main goals in the management of cSLE patients, including sive treatment for all patients. Routine non-live vaccina-
early diagnosis, multidisciplinary approach, and aggressive tions are strongly suggested for all children and adolescents
treatment. with cSLE, such as influenza, tetanus, hepatitis A and B,
meningococcal, pneumococcal, quadrivalent human papil-
lomavirus vaccinations, and COVID-19 [115, 116]. Live
5 Management Data and Drugs for cSLE attenuated immunizations (such as varicella-zoster; measles,
mumps and rubella; and yellow fever vaccines) are gener-
The goals of cSLE treatment are to alleviate signs and ally not indicated for immunosuppressed cSLE patients [2];
symptoms, control disease activity, minimize drug-induced however, no severe events with live-attenuated viruses were
adverse events, prevent long-lasting damage, and improve reported in a case series of vaccinated cSLE patients under
health-related quality of life. Immunomodulation and immunosuppressive agents, after the measles, mumps and
rubella and varicella-zoster booster vaccinations [117]. Non- patients with arterial hypertension or with proteinuria (urine
live vaccines against COVID-19 may be used in young and protein:creatinine ratio > 50 mg/mmol) [124, 127, 128]. A
adult patients with rheumatic diseases under immunosup- recent study demonstrated that the combination of ACE-I
pressive/immunomodulating therapy [118]. The potential and ARB had good tolerability and was without significant
risks of vaccines against COVID-19 remain unknown for adverse events in adult SLE, such as worsening of renal
adult-onset SLE patients and the optimal dose for efficacy function and hyperkalemia [126].
may be different from that in healthy subjects, however, the Physical activity should be recommended for cSLE treat-
risks of not receiving the immunization are far greater cur- ment on a routine basis [129]. Pinto et al. showed that cSLE
rently [119]. Preliminary data for one COVID-19 immu- patients, including those with mild and inactive disease, had
nization (messenger RNA vaccine) in a placebo-controlled impaired aerobic capacity and reduced health-related quality
trial of 2200 adolescents aged 12–15 years showed 100% of life parameters compared with healthy controls matched
efficacy and a strong immune response [120]. This may be by physical inactivity, age, sex, and body mass index [130].
relevant to efforts to control the pandemic, since this group Management issues related to mental health, particularly
of patients may have a role in viral transmission [121] and anxiety, depression, and ineffective family coping, are fre-
a distinct phenotype from adults with less symptomatic quent in children and adolescents with cSLE or lupus nephri-
disease [122]. Further studies to confirm these data and to tis patients and may impact their health-related quality of
assess the medium and long-term effectiveness and safety of life [131, 132]. Although there is a lack of controlled stud-
the COVID-19 vaccine in pediatric rheumatic diseases are ies assessing mental issues in cSLE, studies report depres-
eagerly awaited since widespread vaccination is the most sion and anxiety symptoms to be present in 37% and 30%
efficacious tool to fight against this global pandemic. Table 1 of patients, respectively [133], and to be more frequent dur-
illustrates vaccines that are indicated and contraindicated in ing the induction phase of the treatment [131]. Identifying
the clinical practice of immunosuppressed cSLE patients. targets for improving mental health care, such as developed
Strict control of blood pressure is periodically required. mental health training for pediatric rheumatologists and
A recent study reported arterial hypertension in approxi- integration of medical and mental health services, was pro-
mately one-third of cSLE patients, almost 3 years after posed by CARRA (Childhood Arthritis and Rheumatology
the disease onset. In multivariate analysis, lupus nephritis, Research Alliance) [132]. Therefore, monitoring and refer-
obesity, and high frequency of extra-renal disease activity rals for mental health staff in cSLE patients are warranted.
were independent predictors of arterial hypertension at base-
line [123]. Prompt adjuvant treatment of arterial hyperten- 5.2 Immunomodulation and Immunosuppression
sion and proteinuria should be recommended for all cSLE
patients [96]. Renin–angiotensin–aldosterone system block- Antimalarial drugs are the backbone of the immunomod-
ade antihypertensive and antiproteinuric effects are particu- ulatory regimen used to treat cSLE patients and are an
larly important in SLE management [124]. Proteinuria is a effective steroid-sparing treatment [134]. The benefits of
strong predictor of long-term renal outcomes [125]; conse- hydroxychloroquine (HCQ) on autoimmune disorders have
quently, angiotensin-converting enzyme inhibitors (ACE-I) been known for many decades [47], and this drug may
and angiotensin receptor blockers (ARB) use is considered a interfere in the inhibition of TLR7 and TLR9 signaling,
renoprotective strategy [126] and recommended for all SLE dendritic cell function, and binding of antiphospholipid
Table 1 Indications and contraindications of vaccine use for cSLE clinical practice
Immunizations Type of vaccine
Non-live vaccines are strongly indicated for immunosuppressed cSLE patients Influenza vaccine
Tetanus vaccine
Hepatitis A and B vaccines
Meningococcal vaccine
Pneumococcal vaccine
Quadrivalent human papillomavirus vaccine
COVID-19 vaccine
Live-attenuated vaccines are generally contraindicated for immunosuppressed cSLE patients Varicella-zoster vaccine
Measles, mumps and rubella (MMR) vaccine
Yellow fever vaccine
COVID-19 2019 coronavirus disease, cSLE childhood-onset systemic lupus erythematosus

antibody-β2-glycoprotein I complexes [135]. The Sin- patients [141]. Furthermore, the glucocorticoid effect on
gle Hub and Access point for pediatric Rheumatology in chondrocytes and the hypothalamic-pituitary-gonadal axis
Europe (SHARE) recommendations for diagnosis and treat- interferes in the developmental stage of adolescence and
ment of cSLE suggest that all cSLE patients should be on impacts final height and puberty [142–144]. In a retrospec-
HCQ regularly [96], and the HCQ prescription is consid- tive cohort of 97 cSLE patients, 23% of the participants were
ered a quality measure indicator for cSLE treatment [136]. classified as having short final height and they had a higher
In line with these recommendations, a recent retrospec- cumulative corticosteroid dose compared with those with
tive inception cohort with 473 cSLE patients showed that normal final height [143]. Rygg et al. showed that delayed
antimalarial exposure 6 months before each visit protected pubertal onset was observed in 15.3% of females with cSLE
against an increase in SDI damage score [108]. Another and 24% of males [144].
study observed that current HCQ monotherapy was asso- Specific immunosuppressives should be customized for
ciated with the absence of damage (SDI score of 0) in a each patient based on disease flare and cSLE severity [2].
cohort of adults with cSLE that assessed long-term clinical Lupus nephritis is the leading cause of morbidity in cSLE
outcomes [109]. patients [22, 109] and immunosuppressive therapy includes
Retinopathy is the most important adverse event of HCQ. induction and maintenance. Recently, the SHARE initia-
The 2016 revision recommendations on screening for HCQ tive [97] and Latin American Group for the Study of Lupus
retinopathy from the American Academy of Ophthalmol- (GLADEL) and Pan-American League of Associations of
ogy proposed a baseline ophthalmologic examination (auto- Rheumatology (PANLAR) published recommendations for
mated visual fields and spectral-domain optical coherence childhood-onset lupus nephritis treatment [18]. For lupus
tomography) for all lupus patients during the first year of nephritis classes I and II, low-dose prednisone and antima-
starting HCQ and annual screening after 5 years. The main larials are first-line therapy [2], and disease-modifying anti-
risk factors for retinopathy are daily dosage > 5 mg/kg (with rheumatic drugs (DMARDs) should be used in the event of
an additional risk annually), renal disease and underlying persistent proteinuria or failure to taper GC after 3 months
retinal disease [137]. In contrast, many pediatric practition- [97]. For lupus nephritis classes III and IV, mycophenolate
ers recommend annual eye screening for cSLE patients, rein- mofetil or intravenous cyclophosphamide (IVCYC) in com-
forced by the SHARE guidelines, especially for those under bination with corticosteroids are recommended as induc-
HCQ treatment [96]. tion therapy, while mycophenolate mofetil or azathioprine
Glucocorticoids (GC) are an effective anti-inflammatory are suggested as maintenance therapy for 3 years [18, 97].
and immunosuppressive drug for cSLE therapy, often neces- For pure membranous lupus nephritis (class V), the SHARE
sary for rapid disease control, and should be limited in dose expert group suggests induction treatment with mycopheno-
and duration to what is clinically necessary. The most impor- late mofetil in combination with low-dose oral prednisone,
tant GC mechanism of action is the activation of cytosolic and mycophenolate mofetil or azathioprine as maintenance
glucocorticoid receptors, interfering in the transcription therapy [97].
of nuclear factor-kB and decreasing the synthesis of pro- Nevertheless, cSLE patients with refractory disease or
inflammatory proteins. Non-genomic pathways of GC also with a severe adverse event to standard therapies require
play an important role in the anti-inflammatory effects, espe- additional treatment [2, 66, 97, 134]. Although there is lim-
cially with high-dose pulse glucocorticoid therapy [138]. In ited evidence for rituximab use in children and adolescents
addition, glucocorticoids stimulate apoptosis in many cell with cSLE, a recent systematic review suggested that this
types, including pDC. However, chronically stimulated pDC B-cell-targeting biologic agent was safe and improved dis-
through TLR7 and 9 are more resistant to glucocorticoid- ease activity, serum and urine disease activity markers, and
induced apoptosis and this contributes to the reduced thera- reduced GC dose in cSLE patients [145]. The SHARE group
peutic activity of oral glucocorticoids. In contrast, intra- also recommended rituximab for refractory lupus nephri-
venous methylprednisolone pulse therapy may normalize tis patients in combination with another DMARD [97].
the IFN signature and is associated with a reduction in the Recently, rituximab was also effective as second-line therapy
number of circulating pDC [139]. Prolonged and high-dose for refractory autoimmune hematological disease in cSLE
use of GC should be strictly avoided due to the significant patients [146], and in a small case series of childhood-onset
adverse events, particularly in children and adolescents [2]. lupus erythematosus panniculitis [147].
Indeed, a recent longitudinal study demonstrated that adults Specific immunosuppression should also be matched to
with childhood-onset disease had significantly higher ster- disease manifestations, not just flare, and overall severity.
oid-related damage compared with those who had disease The combination of cyclophosphamide and rituximab has
onset after 18 years old (OR 1.7, 95% CI 1.1–2.8) [140]. been reported more widely in cSLE [148]. Another case
Dosages of GC ≥ 7.5 mg/day were associated with cataract, report involving three cases demonstrated that a combina-
osteoporotic fractures, and cardiovascular damage in SLE tion of rituximab and abatacept was a strategy for repetitive
B-cell depletion in children and adolescents with severe Calcineurin inhibitors (cyclosporine, tacrolimus, voclo-
autoimmune diseases, including two cSLE patients [149]. sporin) have both immunomodulatory and non-immune-
Belimumab is a monoclonal antibody that blocks the mediated roles in treating SLE. They inhibit T-cell prolif-
binding of soluble BLyS to B cells. This B-cell pathway- eration in addition to non-immunological effects that reduce
targeting agent was recently approved by the US Food and proteinuria, including podocyte cytoskeleton stabilization
Drug Administration (FDA) for cSLE treatment in children and afferent arteriole vasoconstriction [158]. According to
> 5 years of age [134, 150]. Importantly, a randomized, the SHARE recommendation, tacrolimus and ciclosporin
double-blind, placebo trial evaluated the efficacy and safety can be an option for selected lupus nephritis patients [97].
of intravenous belimumab (10 mg/kg) plus standard therapy Calcineurin inhibitors have been studied within a multi-
versus placebo in cSLE patients. The main exclusion criteria target treatment in proliferative lupus nephritis, particularly
were active neuropsychiatric lupus, acute severe lupus renal in the Asian population. In a randomized controlled trial
involvement, and prednisone > 1.5 mg/kg/day. A greater including 368 SLE patients also treated with intravenous
proportion of patients receiving this biologic therapy met methylprednisolone pulse therapy and oral prednisone, the
the primary efficacy endpoint of SLE responder index overall response was higher in SLE patients receiving 24
(SRI4) response rate (52.8% vs 43.6%; OR 1.49 [95% CI weeks of mycophenolate mofetil (1 g/day) plus tacrolimus
0.64–3.46]). The improvement in Pediatric Rheumatol- (4 mg/day) versus those receiving intravenous cyclophos-
ogy International Trials Organization/American College of phamide (84% vs 63%). The incidence of adverse events
Rheumatology (PRINTO/ACR) response using 50 defini- was similar in both groups [159]. Voclosporin has been
tions was also significantly higher in the belimumab group studied in a phase II, multicenter, randomized, double-
(60.4% vs 35.0%; OR 2.74 [95% CI 1.15–6.54]). Serious blind, placebo-controlled trial of induction therapy for lupus
adverse effects were observed in 17% of the belimumab nephritis, in combination with mycophenolate mofetil and
group and 35% of the placebo group, and none of them rapid corticosteroid tapering. Among 265 geographically
developed anti-belimumab antibodies. However, a limitation diverse lupus nephritis patients at 6 months, the multi-target
of this study was the small sample size to identify a statisti- therapy achieved superior remission rates (27–33%) com-
cally significant difference in the primary outcome [151]. pared with placebo (19%); however, higher rates of adverse
The use of belimumab for cSLE patients was reported by events including death were reported [160]. A meta-analysis
11% (18/161) of surveyed Latin America Pediatric Rheuma- of 45 randomized trials involving 4222 SLE patients with
tologists [19]. Further multicenter and multinational studies proliferative lupus nephritis, including children and adoles-
with this biologic drug in a large cSLE population will be cents with cSLE, also showed higher remission rates with
required. mycophenolate mofetil, calcineurin inhibitors, and their
There are new therapies targeting CD20 in SLE patients. combination than with intravenous cyclophosphamide.
Atacicept and telitacicept are anti-CD20 monoclonal anti- Mycophenolate mofetil was the most effective maintenance
body agents that inhibit both BAFF (B-lymphocyte Activat- treatment [161]. Furthermore, in a randomized trial of 28
ing Factor of the tumor necrosis factor Family) and APRIL SLE patients with pure membranous lupus nephritis, greater
(A PRoliferation-Inducing Ligand), both are relevant B-cell response rates at 6 months were reported with glucocorticoid
regulator cytokines, and anti-BAFF and APRIL therapies and tacrolimus compared with SLE patients with glucocor-
seem to be promising drugs for SLE patients [152]. ticoid and mycophenolate mofetil (100% vs 75%) [162].
Anti-IFN therapies, such as sifalimumab (anti-IFN-α Therefore, although longer-term outcomes are required,
monoclonal antibody) and anifrolumab (a monoclonal anti- calcineurin inhibitors seem to be a good option for cSLE
body that binds to a type I IFN receptor) have shown ben- patients with lupus nephritis.
eficial results in phase II randomized control trials in adult Table 2 includes the main steroid-sparing immunomodu-
SLE patients with moderate-severe disease versus placebo latory and immunosuppressive agents used in clinical prac-
in addition to standard-of-care medications, without severe tice for the management of cSLE patients. Serious adverse
nephritis and neuropsychiatric involvement [153–155]. A events are an important aspect of clinical care, counseling,
recent case report of three cSLE patients allergic to rituxi- and monitoring for cSLE patients. The most relevant major
mab demonstrated that ofatumumab, a fully humanized serious adverse events of immunosuppressive agents are
anti-CD20 monoclonal antibody, was a safe, well tolerated, found with azathioprine (infection and bone marrow sup-
and effective alternative for B-cell depletion [156]. Another pression), methotrexate (hepatotoxicity, gastrointestinal
report suggested Janus kinase (JAK) inhibitors as an alter- intolerance, and bone marrow suppression), mycophe-
native treatment for pediatric patients with severe IFN- nolate mofetil (infection, bone marrow suppression),
mediated inflammatory disorders, including cSLE patients, cyclophosphamide (infection, decreased ovarian reserve,
reducing progressively inflammatory markers, IFN score, sperm abnormalities, bone marrow suppression, malig-
and inducing upregulation of the DNA repair pathway [157]. nancy), rituximab (infection, infusion reaction, persistent
Table 2 The main steroid-sparing immunomodulatory and immunosuppressive agents used in the clinical practice of cSLE patients
Medications Usual dose Major indications Major serious adverse events
a
Hydroxychloroquine 5 mg/kg/day (maximum 400 mg/day), All patients without contraindication Retinopathy
orally [126]
Azathioprine 2–3 mg/kg/day (maximum 150 mg/ Steroid-sparing for mild/moderate Infection
day), orally disease
Maintenance therapy in LN [18, 96] Bone marrow suppression
Methotrexate 15–20 mg/m2/week orally or subcutane- Steroid-sparing in mild/moderate dis- Hepatotoxicity
ously ease, especially with musculoskeletal GI intolerance
involvement [67, 95]
Bone marrow suppression
Mycophenolate mofetil 1200–1800 mg/m2/day (maximum Induction and maintenance therapy in Infection
3000 mg/day), orally proliferative and membranous LN
Neuropsychiatric disease Bone marrow suppression
Steroid-sparing in moderate/severe
disease [18, 95, 96]
Cyclophosphamide 500 mg/dose (six doses, every 2 weeks, Severe disease Infection
therapy duration of 3 months) OR Induction therapy in proliferative LN Decreased ovarian reserve
500–750 mg/m2/dose (6 monthly [18, 95, 96] Sperm abnormalities
doses), intravenous, therapy duration
of 3 years Bone marrow suppression
Malignancy
Rituximab 750 mg/m2 (2 doses, with interval of 14 Severe and refractory disease [95, 96, Infection
days) OR 129, 132] Infusion reaction
375 mg/m2/week (4 doses with interval
Persistent hypogammaglobulinemia
of 7 days), intravenous, therapy dura-
tion of 1 month
Belimumaba,b 10 mg/kg every 4 weeks, intravenous Clinically active disease, without active Infection
neuropsychiatric cSLE or acute severe
lupus renal involvement [134, 135]
cSLE childhood-onset SLE, GI gastrointestinal, LN lupus nephritis, SLE systemic lupus erythematosus
a
Treatment formally approved for adults with SLE
b
Treatment formally approved for cSLE
hypogammaglobulinemia), and belimumab (infection) [1, lupus nephritis [125]. Another study demonstrated that both
2, 13, 151, 163] (Table 2). proteinuria and serum creatinine levels at 1 year were impor-
tant to predict relevant long-term outcomes in lupus nephri-
tis, while urinalysis did not add value [168].
6 cSLE Prognosis Factors In cSLE populations, decreased creatinine clearance rate
and low C3 complement levels with high serum creatinine
Knowledge of cSLE prognosis factors is relevant to dis- levels were associated with end-stage renal disease [169].
ease management since predictive factors of the long-term A recent study, including 26 previous reports, showed that
renal outcome at early stages of SLE are important to define high serum creatinine (> 1.5 mg/dL) at disease presentation
clinically relevant targets of drug intervention [164]. Three was the major prediction factor for progression to end-stage
laboratory or urinalysis tests have been used regularly in renal disease [170]. Furthermore, high titers of anti-dsDNA
clinical practice as noninvasive predictors for cSLE renal antibodies have modest accuracy to predict lupus nephritis
involvement: kidney function (serum creatinine levels and [171].
measurement of glomerular filtration rate), urinary protein Novel urinary and serum non-invasive biomarkers were
excretion, and glomerular hematuria [15, 165]. reported to be promising parameters to predict disease out-
Early decrease of 24-hour proteinuria (< 0.8 g/day) is come, disease activity, and to estimate chronic kidney dam-
the best predictor of long-term nephritis outcome in SLE age in adult and cSLE patients [165]. A prospective study
patients, based on two previous trials in adult lupus nephritis in cSLE patients with nephritis showed that urinary NGAL
[166, 167]. Decreased proteinuria at 1 year of follow-up was (neutrophil gelatinase-associated lipocalin) was a predictor
also the only predictor of renal outcome at 7 years observed of impaired renal disease activity, contrasting with urinary
in a Latin American SLE group with severe biopsy-proven monocyte chemo-attractant protein 1 (uMCP1) that was a
predictor of improved lupus nephritis [172]. Another lon- support, health education strategies, and adherence inter-
gitudinal report assessed whether urinary levels of ten bio- ventions may help cSLE teens to increase compliance with
markers were related to chronic kidney damage in pediat- treatment [37, 174, 176, 181, 182].
ric lupus nephritis. Renal functional impairment was more
evidenced in cSLE patients with persistent high levels of
transforming growth factor-β (TGFβ), transferrin, and liver 8 Conclusions
fatty acid-binding protein (LFABP), indicating persistent
renal inflammation. Levels of osteopontin and adiponectin cSLE is the prototype of a multisystemic, chronic, inflamma-
measured at the time of kidney biopsy in cSLE patients are tory, and heterogeneous autoimmune condition. This disease
good predictors of histological damage with lupus nephri- is characterized by concomitant or further organ and system
tis [173]. Comorbidities in cSLE patients, such as arterial involvement, with unpredictable flare and high morbimortal-
hypertension or diabetes mellitus, may also alter the excre- ity. Whole exome or whole genome sequencing should be
tion of urinary and serum non-invasive biomarkers, even in considered for cSLE patients to exclude monogenic lupus,
the absence of histologic changes [165]. Further longitudinal particularly in those with early onset of manifestations. Con-
and multicenter studies will be necessary to identify and val- sultation with a geneticist or genetic counselor for such test-
idate these biomarkers for disease activity monitoring and to ing should be recommended. Age subgroups may help cSLE
predict disease severity in different renal histology patterns. 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
7 Drug Adherence for Adolescents provisional criteria for global flares and a provisional index
of clinically relevant improvement have been developed for
cSLE patients are mainly in the adolescence period [20]. cSLE patients. Nonadherence to medication in cSLE ado-
This transitional phase to adulthood involves several physi- lescents was identified as one of the most relevant issues in
cal and emotional changes [37], and the impact of this clinical practice. Belimumab was recently approved by the
complex disease may affect their self-management and FDA for cSLE treatment in children aged > 5 years. Recog-
self-esteem [174, 175]. In fact, a cSLE study in adolescents nition that cSLE is a potentially aggressive disease with high
and young adults with a semi-structured interview showed morbidity and mortality rates is an essential step towards the
that the use of medication served as reminders of their ill- development of safer and more efficacious treatments. The
ness and made them feel abnormal [176]. Nonadherence to treat-to-target principle and tailored medicine approaches
medication in cSLE adolescents was a relevant issue in clini- are novel paradigms for treatment and should also be stand-
cal practice, reported by 97% of Latin American pediatric ardized for pediatric lupus patients.
rheumatologists [19].
There are factors associated with nonadherence to drug Declarations
therapy in cSLE and other chronic rheumatic conditions,
including forgetfulness, low socioeconomic status, family Funding Our study was supported by grants from Conselho Nacional
de Desenvolvimento Científico e Tecnológico (CNPq 305798/2020-0
disruption, polypharmacy, and psychiatric comorbidities
to M-CS, 305242/2019-9 to EB and 304984/2020-5 to CAS), Fundação
[37, 177, 178]. Poor compliance contributes to negatives de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2015/03756-4
outcomes and decreases the health-related quality of life to EB and CAS) and by Núcleo de Apoio à Pesquisa “Saúde da Criança
[179–181]. Scalzi et al. created an online educational pro- e do Adolescente” da USP (NAP-CriAd) to MCS and CAS.
gram for a cohort of SLE adolescents and young adults. The
percentage of drug adherence using web-based education Conflict of Interest The authors declare no conflict of interest regard-
ing this manuscript.
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
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Pediatric Drugs (2021) 23:331–347

An Update on the Management of Childhood‑Onset Systemic Lupus

Accepted: 9 June 2021 / Published online: 10 July 2021

1 Introduction involvement, with unpredictable flare and high morbimor-

degradation and removal of chromatin produced during 3 Childhood‑Onset Systemic Lupus

COVID-19 2019 coronavirus disease, cSLE childhood-onset systemic lupus erythematosus

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Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Update Management of SLE Vitor

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Update Management of SLE Vitor

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Update Management of SLE Vitor

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Pediatric Drugs (2021) 23:331–347

An Update on the Management of Childhood‑Onset Systemic Lupus

Accepted: 9 June 2021 / Published online: 10 July 2021

1 Introduction involvement, with unpredictable flare and high morbimor-

degradation and removal of chromatin produced during 3 Childhood‑Onset Systemic Lupus

COVID-19 2019 coronavirus disease, cSLE childhood-onset systemic lupus erythematosus

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

degradation and removal of chromatin produced during 3 Childhood‑Onset Systemic Lupus