A small Chinese study including 70 JSLE and adult SLE patients (all >16-years old, mean age of the study population not specified) has compared maintenance tacrolimus and azathioprine treatment, showing similar, low LN relapse rates in both treatment arms, with tacrolimus demonstrating a more favorable safety profile than azathioprine. In another small study from China, 26 patients with LN and persistent proteinuria of >1.5g/24-h despite treatment with cyclophosphamide (>8 g in <6-months), were commenced on 2-3mg of tacrolimus daily. 23/26 patients demonstrated an overall renal response (10 complete and 16 partial renal response). Most patients had biopsy confirmed LN (class III=5, class IV=2, class V=5, class III+V=7, class IV+V=4 and unknown n = 3), with patients with class V LN demonstrating higher rates of remission (Table 4). Further research is required in JSLE to evaluate the role of tacrolimus in studies that are sufficiently powered.
In a small randomized controlled trial including 18 JSLE and SLE patients (mean age 29-years) with WHO class III/IV LN, no additional effect was seen in those treated with human umbilical cord-derived mesenchymal stem cells over and above standard immunosuppression (intravenous methylprednisolone and cyclophosphamide followed by maintenance oral prednisolone and MMF, Table 4). The trial was stopped early when it became clear that it would not demonstrate a positive treatment effect.
New evidence relating specifically to each of the SHARE LN recommendations is very limited. Where new evidence could be identified from pediatric, young adult or adult SLE studies it is summarized below.
SHARE recommends that "Immunosuppressive treatment should be guided by a diagnostic renal biopsy". No new original research studies could be identified that relate to this. However, very similar statements have also been endorsed by the Joint EULAR and European Renal Association European Dialysis and Transplant Association (ERA-EDTA) recommendations for the Management of Adult and Pediatric Lupus Nephritis, and the American College of Rheumatology (ACR) Guidelines for Screening, Treatment, and Management of Lupus Nephritis.
When assessing response to initial LN induction treatment, SHARE recommends that "Partial renal response should be achieved preferably by 6 months but no later than 12 months following initiation of treatment" and that "Treatment should aim for complete renal response with urine protein:creatine ratio<50 mg/mmol and normal or near-normal renal function (within 10% of normal GFR)". Again, there is no new pediatric evidence relating to this recommendation. An adult SLE study has since suggested that partial renal response should be achieved sooner (by 12-weeks after commencement of induction therapy for class III or IV LN), with lack of a partial renal response by 12-weeks ultimately predicting poor renal response, and damage accrual. These authors have also shown that early achievement of a complete renal response (by 12-weeks) is significantly associated with maintaining a complete response at 3-years (p = 0.012), less frequent SLE flares (p = 0.026) and damage (p = 0.029) during the subsequent 10-years of follow-up, highlighting the need for assessment for and importance of timely achievement of partial and complete renal response. Further studies are needed to investigate the achievability and impact of such renal outcomes in JSLE.
The SHARE recommendations advocate that "In case of LN with proteinuria, ACE-inhibitors or ARBs should be considered as additional treatment. Combined use of ACE inhibitors and ARBs should be guided by pediatric nephrologists". No new original evidence relating to this recommendation could be found. However, the Brazilian Society of Rheumatology consensus guidelines for the diagnosis, management and treatment of LN in adult SLE have also concluded that "ARBs and ACE inhibitors should be used as antiproteinuric agents unless contraindicated".
In relation to the treatment of class I LN, SHARE recommended that "Low-dose prednisone (<0.5 mg/kg/day) could be considered in class I LN, although treatment choice should be guided mainly by other clinical features" and that "For the treatment of class I LN alone, adding a DMARD is not necessary". This is echoed by the pediatric Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group clinical practice guideline for glomerulonephritis that were published in 2012 (subsequent to the original SHARE literature review), suggesting that patients with class I LN should be treated according to their extrarenal JSLE manifestations. For the treatment of class II LN, SHARE made the following recommendations: "First line treatment of class II LN should be prednisolone (with a starting dose of 0.25-0.5 mg/kg/day, with a maximum of 30 mg/day) tapering over a total duration of 3-6 months" and "For the treatment of active class II LN, a DMARD is necessary in persistent proteinuria and/or when failing to taper corticosteroids after 3-months of low dose prednisolone". Unfortunately, no new evidence could be found in relation to these recommendations.
For induction treatment for class III/IV LN, with or without class V, SHARE recommended "MMF or intravenous CYC, in combination with corticosteroids". This is supported by the recent observational study from the UK JSLE Cohort Study (discussed above) which showed comparability between MMF and cyclophosphamide as induction treatments in JSLE. From the adult SLE literature, a large randomized trial (n = 362, mean age 31.9-years) has demonstrated improved rates of complete and partial renal remission at 24-weeks in patients treated with low-dose MMF, tacrolimus, and steroids compared to monthly intravenous cyclophosphamide and steroids for proliferative LN induction treatment.
The SHARE recommendations also advised that "maintenance treatment for class III or IV LN should consist of MMF or Azathioprine, for at least 3-years". No new pediatric evidence could be found relating to maintenance therapy. However, the American College of Rheumatology also recommends MMF or Azathioprine for maintenance treatment (in addition to low-dose prednisolone), and the pediatric KDIGO guidelines suggest a calcineurin inhibitor can be used for maintenance therapy if a patient is intolerant to MMF or Azathioprine. There was no new evidence guiding the length of maintenance treatment for proliferative LN, or on the treatments that should be used for pure class V LN. Adequately powered randomized controlled trials looking at conventional LN induction and maintenance therapies, investigating of the role of calcineurin inhibitors, and looking at treatment of class V LN in isolation are therefore warranted.
Five of the SHARE recommendations relate to treatment of LN flares and refractory disease. No new evidence could be found relating to these recommendations. All the new evidence relating to LN SHARE treatment recommendations is summarized in Supplemental Table 1.
Despite this extensive literature search, no papers met the inclusion criteria for this section of the review. It is recognized that management of pediatric APS remains challenging due to a lack of large-scale prospective studies, with most treatment recommendations based on adult studies. Hydroxychloroquine is thought to have anti-thrombotic properties. In asymptomatic patients with persistently positive antiphospholipid antibodies, the use of low dose aspirin is controversial, with one small placebo-controlled trial showed no benefit after 2-years. For those who have already suffered from a thrombosis, the main goal of treatment is to prevent further thrombosis through treatment with long term anti-coagulation therapy such as warfarin. The role of immunosuppressive treatment remains uncertain.
A further literature search was performed specifically reviewing for new evidence relating to each SHARE management recommendation for pediatric APS and CAPS. No new evidence could be found relating to the specific management for pediatric APS. A case series of 21 patients with pediatric CAPS (from 1990 to 2013) was found, which suggested that immunosuppression with corticosteroids or rituximab may confer survival benefit. In this study, none of the patients who received rituximab died, however, the odds ratio for survival crossed 1 and was not statistically significant, potentially likely relating to the small sample size. Case reports have also suggested ecluzimab may be beneficial in treatment of CAPS in adults however this has not yet been assessed in children.
This review highlights that treatment paradigms in JSLE are often needing to be extrapolated from adult SLE, whilst RCTs in JSLE are particularly scarce, especially any that are sufficiently powered to demonstrated statistical significance. Most available treatment options are not targeted (conventional DMARDs), and known to cause significant associated adverse events and toxicity, particularly in vulnerable children and young people. Although biologic therapies are used extensively for many autoimmune conditions, there have been several notable setbacks in developing a robust evidence base for SLE, with only belimumab so far licensed for use in SLE in the past 50-years. Difficulties with definitions and use of outcome measures in SLE clinical trials have contributed to these setbacks. The Belimumab in JSLE (PLUTO trial) summarized above raises important questions about the applicability of adult SLE outcome measures in JSLE. In this trial, the adult SLE primary outcome measure (SRI4) was not met in the pediatric age group, but the pediatric-derived major secondary outcome measure (PRINTO/ACR 30, 50) was achieved. Given the known differences in disease activity, severity and damage demonstrated between pediatric, adolescent, and adult SLE, it is important that lessons are learnt from such studies.
Most of the more recent published evidence relate to treatment of LN, with a marked dearth of studies on NP-JSLE and APS. T2T approaches are hoped to offer an opportunity to improve further the clinical management of JSLE patients by using existing treatments in a structured way with the aim of more aggressively controlling disease activity at an early stage, preventing organ damage and improving HRQOL. Such approaches are already part of routine clinical care in many areas of adult medicine (e.g., rheumatoid arthritis, hypertension, diabetes), with growing international evidence for the potential role of T2T in JIA in recent years. Development and testing of such an approach as part of the TARGET LUPUS research programme is eagerly awaited.