Childhood-onset systemic lupus erythematosus

an update

Abstract

Purpose of review 

This is an update of the main studies published in the last year regarding biomarkers, advances in pathophysiology, lupus nephritis as well as outcomes and therapies in childhood-onset systemic lupus erythematosus (cSLE).

Recent findings 

Some progress in the pathophysiology of cSLE was made in the past year. Although biomarkers were studied in lupus nephritis and neuropsychiatric lupus, none of the proposed biomarkers was shown to be a significant improvement over current disease measures. More encouraging was the research into creating an easy, rapid screening tool for neurocognitive dysfunction in cSLE. Two studies in health-related quality of life (HRQL) recognized its importance in determining outcome and found that ethnicity and obesity might significantly alter HRQL in cSLE patients. There were no prospective clinical trials involving cSLE patients.

Summary 

A better understanding of pathophysiology may elucidate novel molecules as therapeutic targets in cSLE. Advances in the field of biomarkers may enable a more accurate prediction of clinical outcome, optimizing early interventions and therefore improving disease prognostics.

INTRODUCTION

Childhood-onset systemic lupus erythematosus (cSLE) is a systemic autoimmune disease characterized by the presence of autoantibodies and multiorgan involvement with onset prior to the age of 18 years. The purpose of this article is to highlight the most important recent advances regarding biomarkers, physiopathology, outcomes and therapies of lupus nephritis in cSLE in the past year.

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IMMUNOPATHOGENESIS AND GENETICS

Exposure to multiple environmental factors in a context of genetic predisposition may trigger autoimmunity resulting in organ damage ^[1▪]. A better understanding of the genetics and inflammatory mechanisms involved in cSLE is essential for the development of new therapeutic strategies.

IMMUNOPATHOGENESIS

A review article in 2014 highlighted the importance of: interferon-alpha (IFN-α) and dendritic cells (DCs); neutrophil activation and necrosis in production of autoantibodies and perpetuation of the autoimmune response and imbalance of T cell subsets favoring a pro-inflammatory environment in the immunopathogenesis of cSLE ^[1▪]. A second review looking at gene profiling reviewed the importance of: IFN signature; innate immunity genes and evidence that intravenous steroids were more effective than oral steroids in decreasing IFN signature ^[2].

Original articles regarding immunopathogenesis are summarized in Table 1. A large study of renal biopsy specimens demonstrated elevated numbers of infiltrating T effector cells in the interstitium and that these cells had activated signal transducer and activator of transcription 3 (STAT-3) leading to the production of the pro-inflammatory cytokine, interleukin (IL)-17 via activation of protein kinase B (PKB) (AKT)/mammalian target of rapamycin (mTOR). As this activation could be inhibited by rapamycin, this study ^[3▪] suggested a potential new therapeutic agent. A second study ^[4] again demonstrated elevated IL-17 in the renal interstitium. A third independent study ^[5] showed decreased interstitial T regulatory cells in biopsies of lupus nephritis patients, which increased to normal levels on repeat biopsy following treatment. These studies demonstrated the importance of immune regulation in the pathogenesis of lupus nephritis.

Table 1: Studies on immunoregulation

Table 1: (Continued) Studies on immunoregulation

Table 1: (Continued) Studies on immunoregulation

Expanding on previous work by their group, Rodriguez-Pla et al.^[6] showed that sera from cSLE patients with the addition of type-1 IFN or lipopolysaccharides (LPS) allowed the acquisition of the DC phenotype on monocytes from healthy individuals. The authors then suggested that as type-1 IFNs are upregulated in pSLE, then flares following infection could be explained by the production of bacterial LPS leading to enhanced DC–T cell interaction and autoantibody production. A second independent study ^[7] suggested that low expression of immune inhibitory receptor leukocyte-associated immunoglobulin (Ig)-like receptor-1 (LAIR-1) on plasmacytoid DCs may be help explain the abnormal IFN-α production seen in patients with cSLE.

Two papers examining the role of microRNAs (miRNAs), endogenous, single-stranded and small noncoding RNAs that regulate multiple genes and functions and are important in maintenance of immune homeostasis, appeared in 2014 ^[8,9]. The first showed that levels of miR-155, an miRNA that leads to increased IL-2 production, were low in cSLE patients and suggested that miR-155 mimics may be used a therapeutic agent to restore abnormal IL-2 production ^[8]. The second study ^[9] found high expression of miRNA-629, miRNA-525–5p and miRNA-516a-3p that correlated with high systemic lupus erythematosus disease activity index (SLEDAI) score; however, the clinical relevance is unknown.

Other studies have explored additional immunological mechanisms leading to cSLE. Elevated levels of IL-17A but not Th1 cytokines or Th2 cytokines were found in the sera of cSLE patients ^[10]. A second study ^[11] examined the role of adipocytes as the source of the TNF-a levels found in cSLE. By comparing circulating TNF-a levels in obese and nonobese cSLE patients, their results suggested that adipocytes may be one source of the elevated serum TNF-α levels. A second study ^[11] examining obese and nonobese cSLE patients suggested that adipocytes may be one source of the elevated serum TNF-α levels found in cSLE. Lastly two articles attempted to reproduce findings seen in adult-onset SLE (aSLE). The first showed that sera from cSLE could induce apoptosis and increase caspase levels of neutrophils from healthy children, supporting previous works suggesting that neutrophils may be a source of autoantigens in SLE ^[12]. Long interspersed nucleotide element-1 (LINE-1) is a retrotransposon that may alter the expression of cytokines including IFN-α. As hypomethylation of LINE-1 was reported to be present in aSLE patients, the other article examined LIN-11 methylation in cSLE and showed decreased methylation of LINE-1 ^[13]. The significance of this finding is not clear.

GENETICS

There were very few genetic studies in cSLE. Two small candidate gene studies ^[14,15] failed to show an association with single nucleotide polymorphisms (SNPs) in IL-10 TGF-β gene, IL-α, IL-1β, IL-1 receptor, IL-1 receptor antagonist or Il-6 genes. There was a case report of a girl with SLE had X polysomy supporting the importance of the X chromosome in SLE susceptibility ^[16]. Two small studies ^[17,18] again showed the importance of type 1 IFNs in familial chilblain lupus associated with three prime repair exonuclease 1 mutations.

BIOMARKERS

Two review articles published in 2014 summarized research into potential biomarkers for both lupus nephritis and neuropsychiatric lupus ^[19,20].

A longitudinal study ^[21] expanded on previous cross-sectional studies of urinary monocyte chemo-attractant protein 1 (uMCP1) showing that uMCP-1 levels decreased prior to the improvement of renal disease and confirmed earlier studies that increases in urinary neutrophil gelatinase-associated lipocalin (uNGAL) preceded a flare of renal disease in cSLE patients. Two small cross-sectional studies ^[7,22] showed for the first time that serum high mobility group box 1 protein (HMGB-1) levels were elevated in cSLE (previously shown in aSLE) and that levels were higher in active versus inactive disease. A small cross-sectional study showed elevated serum soluble receptor for advanced glycation end-products in cSLE patients ^[7,22] (Table 2).

Table 2: Biomarker studies

Table 2: (Continued) Biomarker studies

A pilot study ^[23] assessed the correlation of a panel of biomarkers and brain-reactive antibodies with neurocognitive dysfunction (NCD). Serum NGAL and S100 proteins, anti-DNA antibodies, anti-NR2 glutamate receptor antibodies, antiribosomal P antibodies and antiphospholipid antibodies were measured in 40 cSLE patients at baseline and 18 months later (only 27 patients). There was a suggestion that antiribosomal P antibody levels were associated with NCD. Increases in levels of NGAL and anti-NR2 antibodies were associated with a decrease in psychomotor speed and working memory, respectively, between the two testing periods.

It is hoped, but not proven, that biomarkers will enable to accurately predict clinical outcomes optimizing early interventions before overt organ damage, reducing the disease progression.

LUPUS NEPHRITIS

Lupus nephritis occurs in nearly 50% of cSLE patients. Although it is clear that patients with proliferative lupus nephritis (PLN) have a worse outcome as compared with other types of lupus nephritis, it is not clear if patients with mixed PLN/membranous have the same outcome as though with pure PLN. A cross-sectional analysis from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry found no significant difference in clinical measures of response and medication exposure between the two groups ^[24]. The second article on lupus nephritis reported a remission rate of 90% in 30 cSLE patients with pure membranous lupus nephritis (MLN) after a median follow-up of 4.69 months (mean baseline 24 h protein excretion was 3.72 g) ^[25▪]. Importantly, 76% of the patients had a sustained remission with low-dose prednisone (<5 mg/day) maintenance. A low albumin level at the time of renal biopsy predicted lower remission rate and longer time to remission.

NEUROCOGNITIVE TESTING

Testing for neurocognitive function is important to determine the extent and impact of CNS involvement. As formal neurocognitive testing is an arduous and labor-intensive endeavor, self-reported questionnaires for screening of neurocognitive dysfunction are important. A cross-sectional study ^[26] of 40 cSLE patients compared the results of one patient-based questionnaire (Subjective Awareness of Neuropsychological Deficits for Children-SAND-C) and two parent/proxy questionnaires (Behavior Rating Inventory of Executive Function-BRIEF and subscales of the Child Behavioral Checklist-CBCL) to formal neurocognitive testing and showed that the self-reported questionnaire did not correlate with formal neurocognitive testing.

On a more encouraging note, there was preliminary validation of a summary score of the Pediatric Automated Neuropsychological Assessment Metrics (PedANAM), a computerized measure of cognitive ability, mental processing speed, memory and cognitive efficiency ^[27]. Hopefully, this will simplify the use of the PedANAM in helping to determine neurocognitive function and if prospectively validated in a larger sample, it may be a relatively easy screening tool to determine global neurocognitive function to determine patients who require formal neurocognitive testing.

HEALTH-RELATED QUALITY OF LIFE

HRQOL, a multidimensional model that includes self-reported measures of physical and mental health, is becoming increasingly recognized as an important outcome in cSLE. A cross-sectional analysis from a nationwide prospective and multiethnic Canadian cohort demonstrated that patients with cSLE (n = 196) endorsed poorer HRQOL as compared with healthy controls and patients with juvenile idiopathic arthritis (JIA). The HRQOL differed between ethnicities and was lower in white versus nonwhite cSLE patients in a context of similar socioeconomic status and SLE activity ^[28▪]. A second report demonstrated that physical functioning was significantly lower in obese as compared with nonobese cSLE children and healthy controls (nonobese and obese) and that the cSLE patients determined to be obese endorsed worse social, school and emotional functioning and more pain when compared with their nonobese counterparts ^[29].

TREATMENT

There were no treatment trials in cSLE but the results of most studies in aSLE can be extra-polated to cSLE. There were two trials of abatacept [cytotoxic T-lymphocyte-associated protein (CTLA)4-Ig] a soluble fusion protein between CTLA-4 and the Fc portion of IgG1 that modulates the CD28–CD80/86 signaling pathway. In a 12-month, randomized, multicenter, double-blind trial, 298 aSLE patients with active PLN (ISN/RPS class III or IV) were randomly assigned to receive standard care [prednisone and mycophenolate mofetil (MMF)] plus placebo, standard care plus abatacept (loading dose of abatacept followed by standard dose) or standard care plus standard dose of abatacept ^[30]. This trial failed to meet the primary endpoint at 52 weeks. Post-hoc subanalysis showed that treatment with abatacept resulted in greater reduction of proteinuria when compared with placebo in the patients who had nephrotic-range proteinuria at baseline. Gastroenteritis and herpes zoster were reported more frequently in abatacept group. A major limitation of this study was that there was no defined glucocorticoid treatment. A post-hoc analysis of this trial adopting less strict treatment response definitions revealed that more patients in the abatacept groups achieved renal response when compared with the placebo group.

A second trial of abatacept, a double-blind, placebo-controlled phase II trial, Abatacept and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS) also failed to demonstrate any benefit of abatacept at 24 weeks when added to a regimen consisting of low dose of IV cyclophosphamide followed by azathioprine in patients with PLN ^[31]. However, 11/22 patients in the abatacept treatment group who met complete response criteria at week 24 were able to achieve a sustained complete response at week 52 without need of further immunosuppressive treatment.

Although two earlier prospective, randomized, placebo-controlled trials of rituximab in aSLE (one in PLN) failed to meet their primary endpoint, many rheumatologists and nephrologists continue to use rituximab. However, data regarding safety and efficacy of rituximab in cSLE are limited. A case series of 48 cSLE patients reported significant improvement in physician's global assessment of disease activity and serologic parameters and a decrease in steroid dosage at 12 months after one course of rituximab ^[32]. However, there were 12 infections requiring hospital admission. A case series of 12 cSLE patients with active or refractory PLN treated with a combined therapy of rituximab and cyclophosphamide for a period of 18 months reported a significant reduction in prednisone dose, erythrocyte sedimentation rate and SLEDAI at 1 year with sustained clinical response throughout a 5-year follow-up. However, two patients required hospital admission due to febrile neutropenia ^[33]. A second small case series (16 cSLE patients with refractory disease received rituximab and IV cyclophosphamide) reported a significant reduction in corticosteroid dose, disease activity (SLEDAI) and increased complement levels at 6 months. A significant infection was documented in two patients, and one patient developed pancreatitis ^[34].

An uncontrolled open-label trial comparing the efficacy of rituximab to conventional therapy for lupus nephritis induction (MMF or cyclophosphamide) for aSLE patients with active nephritis failed to show any difference among the groups in terms of renal response, serologic parameters or extra-renal manifestations at 3 and 12 months. In addition, there were no differences beyond 12 months of follow-up except for more renal flares in the cyclophosphamide arm ^[35].

A systematic review reported on 26 studies (one randomized controlled trial, two open-label trials and 22 prospective and retrospective cohort studies) examined the efficacy and safety of rituximab for the treatment of nonrenal SLE refractory to conventional therapy. This analysis of 1231 aSLE patients found an improvement in arthritis, thrombocytopenia, complement and anti-dsDNA levels with a steroid-sparing effect (level of evidence: 2b, 2c and 4; grade of recommendation: B and C) ^[36]. There was limited evidence for efficacy in the treatment of anemia, or cutaneous and neuropsychiatric involvement. The most frequent adverse events were infusion reactions and infections with an estimated incidence of serious infections at 6.6–12.6/100 patient-years. The main limitations of this systematic review were that uncontrolled studies were included and that there was a heterogeneous definition of outcomes among the studies.

In addition to the previously mentioned adverse events, a case report emphasized the potential importance of the previously recognized early onset neutropenia (within 4 weeks of initiation of rituximab therapy) ^[37] that may increase the risk of severe infections including pneumocystis jirovecii pneumonia ^[38].

Belimumab, the first biologic approved for refractory SLE, binds and inhibits the soluble human B lymphocyte stimulator protein (BLyS). Two earlier randomized, placebo-controlled phase III trials demonstrated the efficacy of belimumab in aSLE. An open-label long-term 7-year extension in a subset of patients from the original studies showed continual disease control with further reduction in median steroid dose by greater than 50% and decrease in severe disease flare rate ^[39]. A small (18 aSLE patients) retrospective study ^[40] with refractory disease reported a reduction in prednisone dose at 9 months and improvement in SLEDAI-2K at 3 months although five disease flares were reported. The majority of infections seen were mild although one patient discontinued treatment because of recurrent upper respiratory infections and an additional two for refractory disease.

Overall belimumab has a good safety profile in long-term studies although one patient on belimumab and MMF died of progressive multifocal leukoencephalopathy (PML) ^[41].

Belimumab has been an important milestone in the development of new biologic therapies for the management of SLE. An ongoing multicenter, randomized, placebo-controlled trial is currently recruiting participants to evaluate the safety, efficacy and pharmacokinetics of belimumab in cSLE (NCT01649765, clinicaltrials.gov).

SLE Responder Index (SRI) is a novel composite outcome used in the both above-mentioned belimumab trials that requires improvement in SLE disease activity without worsening in specific organ domains or global disease activity. A post-hoc analysis including 1684 aSLE patients from the Study of Belimumab in Subjects with SLE (BLISS) trials, demonstrated that SRI responders (n = 761) at 52 weeks reported greater improvement from baseline in clinical, serological parameters and patient-reported outcomes (fatigue and HRQOL) as well as greater reduction in corticosteroid dose and rate of disease flares when compared with non-SRI responders ^[42]. This may indicate that SRI response, initially developed to define meaningful changes in disease activity in the BLISS trials, is associated with a more comprehensive clinical improvement in patients with active SLE beyond these components measured by the SRI.

CONCLUSION

Despite the recent advances on physiopathology, there is still a need for the implementation of interventional therapeutic trials in cSLE. Unfortunately in 2014, there were no major advances in biomarker discovery and to date they have not consistently been shown to improve on the current measures of disease activity. However, future studies, including clinical trials, will improve the predictive of value of both serum and urinary biomarkers.

Acknowledgements

This manuscript has been seen, reviewed and approved by all contributing authors.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest
• ▪▪ of outstanding interest