International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis

Abstract

Objective: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology.

Methods: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%.

Results: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6).

Conclusion: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

Figure 1.. Development of the Standardized Steroid dosing Regimen (SSR) for childhood-onset SLE.

The experimental design used can be summarized in Step-1 to Step-6, and consists of various consensus formation methods, statistical analyses and the use of real-life data from pediatric patients with LN in Patient Profile ratings. Abbreviations used are: Oral-CS: oral corticosteroids; IV-CS: intravenous corticosteroids; CARRA: Childhood Arthritis and Rheumatology Research Alliance; PP: patient profiles; LN: lupus nephritis; REDCap is a browser-based, metadata-driven electronic data capture software and workflow methodology for designing clinical and translational research databases; for additional details please see: https://projectredcap.org/software

Figure 2.. Operational definitions for changes in the lupus nephritis response variables for use in the SSR.

A: Estimated glomerular filtration rate (eGFR) of ≥95 ml/min/1.73 m² was considered to be normal, and abnormal for eGFR values < 95 ml/min/1.73 m², irrespective of patient age. B: Values of the urine protein creatinine ratio (UPCR) from a random urine sample were considered normal for values ≤ 0.2 mg/mg and abnormal for values >0.2 mg/mg. Changes of the UPCR of ± 0.3 were deemed to represent stable proteinuria. Examples of changes of the UPCR between Visit 1 and Visit 2 and assessment of UPCR status are as follows: 0.5→0.25 (decrease by 50%, but decrease is <0.3, so UPCR is stable); 0.5→0.2 (UPCR normal); 0.5→0.8 (increase by >50% and increase by 0.3, so UPCR is worse); 0.5→0.75 (increase by 50%, but increase is <0.3, so UPCR is stable). C: Only glomerular hematuria was considered when assessing urine microscopy, whereas pyuria and cellular casts were omitted. Five categories of glomerular hematuria measures in RBC/High Power Field (HPF) were defined as follows: normal: 0–5 RBC/HPF; mild: 6–10 RBC/HPF; moderate: 11–25 RBC/HPF; severe: 26–50 RBC/HPF; gross: >50 RBC/HPF.

Figure 3.. Examples of SSR suggested changes in prednisone (or equivalent dose of another corticosteroid).

A: Suggested prednisone dose adjustment of a cSLE patient (≥ 40 kg) whose kidney biopsy showed proliferative lupus nephritis within the preceding 12 weeks. Upon re-assessment, the patient was taking prednisone 30 mg daily, his renal course was “Active-improved” and extra-renal disease course “Active-much worse”. The SSR recommends increasing daily prednisone dose to 40 mg. If tolerated, tapering oral-CS during the subsequent 4 weeks post assessment to 35 mg is proposed. B: Suggested prednisone dose adjustment of a cSLE patient (≥ 40 kg) who completed induction therapy for LN, and achieved at least partial renal remission at week 26. Upon re-assessment, the patient was taking prednisone 30 mg daily and having a “LN flare after PRR”. The SSR recommends increasing the daily prednisone dose to 60 mg, irrespective of the extra-renal course. If renal response is improved with higher oral-CS doses, then oral-CS tapering can be initiated at day 10. The minimum allowable daily prednisone dose at day 30 following LN flare is 40 mg. If the patient has not improved by day 10, then intravenous pulse methylprednisolone (1–3 doses) should be considered.