Childhood-onset Lupus Nephritis Initial Glucocorticoid-dose Harmonization Trial (LIGHT Trial)

CRR is defined as meeting both of the following criteria: (1) Urine protein <0.5 g/1.73 m², or 24-hour urine protein <300 mg/m², or urine protein-to-creatinine ratio (UPCR) <0.5 g/g; AND (2) Estimated glomerular filtration rate (eGFR) within the normal range; or eGFR at least 85% of baseline; or normal serum creatinine with an increase of no more than 25% from baseline.

PERR is defined as meeting both of the following criteria: (1) UPCR <0.7 g/g; AND (2) eGFR at least 80% of baseline or eGFR ≥60 mL/min/1.73 m².

PRR is defined as meeting both of the following criteria: (1) Urine protein reduced by ≥50% from baseline and UPCR <3 g/g; AND (2) eGFR at least 85% of baseline.

Total renal response (TRR) is defined as achievement of complete renal response (CRR), primary efficacy renal response (PERR), or partial renal response (PRR). Complete renal response (CRR) is defined as meeting both of the following criteria: 1. Proteinuria <0.5 g/1.73 m², or 24-hour urinary protein excretion <300 mg/m², or urine protein-to-creatinine ratio (UPCR) <0.5 g/g; and 2. Estimated glomerular filtration rate (eGFR) within the normal range, or eGFR ≥85% of baseline, or a normal serum creatinine level with an increase of no more than 25% from baseline. Primary efficacy renal response (PERR) is defined as meeting both of the following criteria: 1. UPCR <0.7 g/g; and 2. eGFR ≥80% of baseline or eGFR ≥60 mL/min/1.73 m². Partial renal response (PRR) is defined as meeting both of the following criteria: 1. A ≥50% reduction in proteinuria from baseline and UPCR <3 g/g; and 2. eGFR ≥85% of baseline.

Complete renal response (CRR) is defined as meeting both of the following criteria: (1) Urine protein <0.5 g/1.73 m², or 24-hour urine protein <300 mg/m², or urine protein-to-creatinine ratio (UPCR) <0.5 g/g; (2) Estimated glomerular filtration rate (eGFR) within the normal range; or eGFR at least 85% of baseline; or normal serum creatinine with an increase of no more than 25% from baseline.

Primary efficacy renal response (PERR) is defined as meeting both of the following criteria: (1) UPCR <0.7 g/g; (2) eGFR at least 80% of baseline or eGFR ≥60 mL/min/1.73 m².

Partial renal response (PRR) is defined as meeting both of the following criteria: (1) Urine protein reduced by ≥50% from baseline and UPCR <3 g/g; (2) eGFR at least 85% of baseline.

To assess the improvement of SLE serum activity

To assess the improvement of SLE serum activity

To assess the improvement of SLE disease activity

To assess the improvement of SLE disease activity

To assess the level of disease activity improvement by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score.

Physician Global Assessment (PGA) is a clinical tool utilizing a 0 to 3 visual analogue scale to measure overall disease activity by experienced rheumatologists.

Parental Global Assessment (ParentGA) is a parent-reported outcome measure used to quantify a caregiver's perception of their child's overall disease impact and well-being. ParentGA consists of a horizontal line containing 21 circles numbered from 0 to 10. The scale moves in 0.5 increments. The score of 0 indicates "very well" (best possible health status/disease activity) and 10 indicates "very poor" (worst possible health status/disease activity).

The Pediatric Quality of Life Inventory (PedsQL) is a modular assessment tool used to measure health-related quality of life in children, evaluating physical, emotional, social, and school functioning to generate an overall health score.

To measure renal function levels

eGFR (estimated Glomerular Filtration Rate) is a calculated value used to assess kidney filtration function. Pediatric eGFR [mL/(min·1.73m2)] = K × 88.4 × Height (cm)/Serum Creatinine (μmol/L).

When serum creatinine is measured using the Jaffe method, the K coefficient is proportional to an individual's muscle mass and varies with age. In adolescents, it varies according to sex:

Children and adolescent females: K = 0.55; Adolescent males: K = 0.77. When creatinine is measured using an enzymatic assay: K = 0.413

A 24-hour urine protein test measures kidney function by quantifying how much protein the body excretes in a full day.

A UPCR (Urine Protein Creatinine Ratio) test measures the amount of protein relative to creatinine in a single urine sample. It is a highly accurate, convenient alternative to 24-hour urine test.

LN treatment failure is defined as the occurrence of any of the following:

1. Death;
2. New-onset end-stage renal disease (ESRD), or the need for dialysis or kidney transplantation;
3. Doubling of serum creatinine (compared with the baseline level);
4. Renal flare, defined by either (a) or (b):
5. Proteinuric flare: after excluding secondary causes such as infection, 24-hour urinary protein excretion or the urine protein-to-creatinine ratio (UPCR) increased to at least twice the baseline level; or
6. Nephritic flare: after excluding secondary causes such as infection, serum creatinine increased by 25% from baseline, together with any of the following:

• 24-hour urinary protein increased to at least twice the baseline level and exceeded 2 g/24 h, or the equivalent UPCR;
• New-onset hematuria graded as 2+ or more;
• New-onset cellular casts.

Renal flare, defined by either (a) or (b):

1. Proteinuric flare: after excluding secondary causes such as infection, 24-hour urinary protein excretion or the urine protein-to-creatinine ratio (UPCR) increased to at least twice the baseline level; or
2. Nephritic flare: after excluding secondary causes such as infection, serum creatinine increased by 25% from baseline, together with any of the following:

• 24-hour urinary protein increased to at least twice the baseline level and exceeded 2 g/24 h, or the equivalent UPCR;
• New-onset hematuria graded as 2+ or more;
• New-onset cellular casts.

SLE flare is defined according to SELENA-SLEDAI definitions:

1. An increase in the SLEDAI score of ≥3 points compared with the previous assessment;
2. New-onset or worsening manifestations of lupus activity, including cutaneous lesions, oral or nasal ulcers, pleuritis, pericarditis, arthritis, fever, neuropsychiatric lupus, vasculitis, nephritis, myositis, platelet count <60 × 10⁹/L, hemolytic anemia (hemoglobin <70 g/L or a decrease of >30 g/L), lupus myocarditis, or lupus pneumonitis;
3. Initiation or dose escalation of medications because of disease activity, including NSAIDs, glucocorticoids, cyclophosphamide, methotrexate, or azathioprine;
4. A Physician Global Assessment (PGA; range, 0-3) score of ≥1.

LLDAS was defined as meeting all of the following criteria:

1. SLEDAI-2K score ≤4, with no activity in major organ systems (renal, neuropsychiatric, cardiopulmonary, vasculitic, or constitutional activity), no hemolytic anemia, and no gastrointestinal activity;
2. No new manifestations of SLE disease activity compared with baseline;
3. SELENA-SLEDAI Physician Global Assessment score (range, 0-3) ≤1;
4. Prednisone dose, or equivalent glucocorticoid dose, ≤7.5 mg/day.

DORIS remission is defined as meeting all of the following criteria:

1. Clinical SLEDAI score = 0;
2. Physician Global Assessment score (range, 0-3) <0.5, irrespective of serological activity;
3. Treatment with antimalarial agents was permitted, as was prednisone at a dose of ≤5 mg/day (or an equivalent glucocorticoid dose) and/or stable immunosuppressive therapy, including biologic agents.

Response was defined as improvement of at least 50% from baseline in any two of the five core outcome measures, with no more than one of the remaining measures worsening by more than 30%.

The five core outcome measures were Physician Global Assessment of overall disease activity (PGA), Parent Global Assessment of disease activity (ParentGA), proteinuria, the SLE Disease Activity Index 2000 (SLEDAI-2K), and the physical functioning domain of the Pediatric Quality of Life Inventory (PedsQL).

The Childhood Lupus Improvement Index (CHILI) is a validated measure of treatment response in childhood-onset SLE that primarily captures clinically meaningful improvement. The score is calculated using five core outcome measures: Physician Global Assessment of overall disease activity (PGA), Parent Global Assessment of disease activity (ParentGA), proteinuria assessed by the urine protein-to-creatinine ratio (UPCR) or 24-hour urinary protein excretion, the SLE Disease Activity Index 2000 (SLEDAI-2K), and the physical functioning domain of the Pediatric Quality of Life Inventory (PedsQL). (PMID: 30680946)

Using the CHILI absolute-change definition, clinical improvement is defined as a CHILI score ≥54; minor improvement as CHILI ≥15; moderate improvement as CHILI ≥68; and major improvement as CHILI ≥92.

The pediatric glucocorticoid toxicity index (pGTI) is a composite index including 10 glucocorticoid toxicity domains: body mass index, growth and development, glucose tolerance, lipid metabolism, systolic blood pressure, bone mineral density, glucocorticoid-induced myopathy, skin toxicity, neuropsychiatric effects, and infection.

(PMID: 35917759)

The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR Damage Index, SDI) is designed to assess cumulative, irreversible organ damage occurring since the onset of SLE. It encompasses 39 types of chronic, irreversible damage across 12 organ systems, irrespective of ongoing inflammatory disease activity. (PMID: 8607884)

Adverse events should be assessed at each study visit, including the event name, timing, management, severity, and outcome.

Adverse event grading:

Grade 1 (mild): Asymptomatic or mild symptoms; clinical or diagnostic findings only; no treatment required.

Grade 2 (moderate): Requires minor or local treatment and limits instrumental activities of daily living.

Grade 3 (severe): Medically significant but not immediately life-threatening; hospitalization may be required; limits self-care activities of daily living.

Grade 4 (life-threatening): Requires urgent intervention. Grade 5 (death): Death related to the adverse event.

To measure improvement of kidney function, and monitor the side effect by glucocorticoids.

To evaluate adverse events of glucocorticoids

To monitor adverse effects of glucocorticoids

To measure the growth velocity of children, and monitor the adverse events of glucocorticoids

To monitor the side effects of glucocorticoids, bone mineral density (BMD) is measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine.