Optimal Glucocorticoid Dosing in Lupus Nephritis?

Lupus nephritis is one of the most frequent severe organ manifestations of systemic lupus erythematosus (SLE), requiring treatment with glucocorticoids, initially with immunosuppressive therapies. However, steroids are associated with infection risk, and the optimal dosing and tapering of steroids in lupus nephritis is largely unknown. While the EULAR guidelines in SLE recommend the use of reduced steroid regimens for lupus nephritis,¹ there are no studies comparing the efficacy and safety of reduced-dose versus standard-dose regimens.

Figueroa-Parra et al performed a recently published systematic review and meta-analysis evaluating the effect of glucocorticoid regimens on renal response, infections, and mortality in patients with lupus nephritis.² They evaluated the control arms of randomized, controlled trials (RCTs) for lupus nephritis with protocolized glucocorticoid regimens. The study included RCTs with 10 or more individuals with biopsy-proven lupus nephritis per arm with a minimum follow-up of 6 months. They required initial therapy with a protocol of steroids in combination with standard-of-care therapy with either mycophenolic acid analogs (MPAA; mycophenolate mofetil 2.00-3.00 g/day or mycophenolic acid 1.44-2.16 g/day) or cyclophosphamide (high-dose 0.5-1.0 g/m² BSA monthly x 6 doses or low-dose 0.5 g every 2 weeks x 6 doses) and subsequent therapy with MPAA or azathioprine. Covidence was used to perform the screening process of abstracts and texts, and the revised Cochrane risk of bias tool for RCTs was used to assess risk of bias.

Outcomes evaluated included complete response (CR; proteinuria <0.5 g/24 hours and stabilization of serum creatinine [+/−25% from baseline]), serious infections (resulting in death, hospitalization, or requiring intravenous antimicrobial therapy), and all-cause death. The glucocorticoid regimen was abstracted. Researchers defined a “low” starting dose as ≤30 mg/day (≤0.5 mg/kg) and a “high” starting dose as >30 mg/day (>0.5 mg/kg) of oral prednisone. The taper speed of steroids was defined as “fast” or “slow” when the prednisone dose at week 16 was ≤7.5 mg/day or >7.5 mg/day, respectively. A steroid pulse was defined as the use of intravenous methylprednisolone ≥250 mg/day. Meta-analysis of proportions, meta-regression, and subgroup meta-analyses were performed; the outcome event rate (proportion of patients achieving CR, developing serious infections, or death) and 95% CIs were estimated at 6 and 12 months for all outcomes.

Of over 5800 studies screened, 37 RCTs met eligibility criteria and 50 individual RCT arms were suitable for meta-analysis. These RCTs included 3231 patients with lupus nephritis. The median pulse doses of methylprednisolone was 750 mg/day, with all but 1 study using pulse doses ranging from 0.5 to 1.0 g/day. Overall, the predicted rates of CR, serious infections, and death when starting oral prednisone 25 mg/day (without pulses) were 19.5%, 3.2%, and 0.2%, respectively. Starting with prednisone 60 mg/day (without pulses) increased the rates to 34.6%, 12.1%, and 2.7%, respectively. The addition of glucocorticoid pulses increased the rates of CR and death, but not serious infections. Researchers observed a dose-response gradient between initial steroid dose and all outcomes at 6 months, after accounting for steroid pulses, underlying immunosuppressant agent, and baseline proteinuria.

The infection rate was 3.2% at 6 months when using prednisone 25 mg/day; the rate tripled to 12.1% when using prednisone 60 mg/day. There was no difference in rate of serious infections at 6 or 12 months when subgrouped by taper speed or use of glucocorticoid pulses. There was no significant difference in mortality between slow versus fast tapers at 6 months, but there was a higher rate of death for fast taper studies (3.7%) versus slow taper (1.4%) at 12 months.

Using protocolized steroid regimens from lupus nephritis RCTs, this meta-analysis demonstrates that higher doses of glucocorticoids are associated with higher rates of CR in lupus nephritis, but at a cost of higher rates of serious infections and death. While the optimal steroid regimen may vary patient to patient, at a population level, the authors noted, there was a disproportionate increase in number of infections and deaths for steroid protocols that began at doses >40 mg/day, while glucocorticoid pulses were not associated with infection to the same degree. Thus, they hypothesized that a steroid protocol with a glucocorticoid pulse with an initial dose of 40 mg/day (0.6-0.7 mg/kg/day) of oral glucocorticoids may be an optimal regimen at a population level. However, the authors emphasized the importance of a more tailored approach for glucocorticoid dosing for individual patients, which may result in some significant variation from this regimen, when accounting for disease severity, weight, and infection risk in individual cases.

This study has some limitations, including no head-to-head comparisons of the different glucocorticoid starting doses. The certainty for findings at 6 months was rated as moderate (CR, serious infection) and low (death), with low or very low certainty for findings at 12 months. Yet the study provides novel, relevant findings for clinical practice in a relatively data-void space: higher doses of steroids in lupus nephritis are more likely to achieve disease remission, but at a cost of serious infections and higher mortality.

References

[1] Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15-29. doi:10.1136/ard-2023-224762

[2] Figueroa-Parra G, Cuéllar-Gutiérrez MC, González-Treviño M, et al. Impact of glucocorticoid dose on complete response, serious infections, and mortality during the initial therapy of lupus nephritis: a systematic review and meta-analysis of the control arms of randomized controlled trials. Arthritis Rheumatol. 2024. doi:10.1002/art.42920