Assessing laboratory markers as biomarkers for renal flare in patients with SLE

Patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) are at risk of developing severe renal complications, with up to 20% developing end-stage kidney disease within 10 years. The identification of biomarkers associated with renal flare could aid kidney monitoring, enabling the risk-stratification of patients and subsequent management changes.

During the American College of Rheumatology (ACR) annual meeting (ACR Convergence 2022), Gomez¹ presented a post-hoc analysis of four phase III trials to assess laboratory markers as biomarkers for renal flare in patients with active SLE.

Study design

The study included four trials with similar designs:

• BLISS-52 (NCT00424476)
• BLISS-76 (NCT00410384)
• BLISS-SC (NCT01484496)
• BLISS-NEA (NCT01345253)

Together, these studies included 3,225 patients with SLE; the primary outcome was development of renal flare. Figure 1 outlines the biomarkers assessed.

aCL, anticardiolipin; ANA, anti-nuclear antibody; ds, double-stranded; Sm, Smith; Ig, immunoglobulin; IV, intravenous; SC, subcutaneous; SLE, systematic lupus erythematosus.
*Adapted from Gomez.^1
†Defined as: proteinuria >6 g/day, creatininemia >2.5 mg/mL, Active biopsy-proven lupus nephritis, or the requirement of hemodialysis 90 days prior to enrolment.
^‡Defined as: increase in proteinuria, increase in serum creatinine, or new onset of hematuria of glomerular origin.

Results

During the analysis period, 192 patients had a renal flare. Patients in the renal flare group were younger; more frequently of Asian origin (p < 0.001); had significantly greater severity of disease activity, measured by Systemic Lupus Erythematosus Disease Activity Index 2000 score; and had experienced more renal involvement, measured by British Isles Lupus Assessment Group (BILAG) renal A-D index, compared with the whole cohort. However, fewer patients in the renal flare group had irreversible organ damage, measured as a Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) >0, compared with those who did not experience renal flare.

Table 1. Baseline patient characteristics* 

BILAG, British Isles Lupus Assessment Group; SD, standard deviation; SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index. *Adapted from Gomez.1
Characteristic, % (unless stated otherwise)	Renal flare (n = 192)	No renal flare (n = 3,033)	p value
Mean age (SD), years	32 (11)	37 (12)	<0.001
Female	91	94	0.127
Ethnic origin
Asian	72	36	<0.001
African American	5	7	0.157
Indigenous American	8	14	0.021
Caucasian	15	42	<0.001
Clinical characteristics
Mean SLEDAI-2k (SD), n	12 (4)	10 (4)	<0.001
Mean SLE duration (SD), years	6 (6)	6 (6)	0.560
SDI >0	44 (23)	1,102 (36)	<0.001
BILAG renal A-D	94	52	<0.001
Mean Prednisone dose (SD),               mg/d	14 (11)	12 (9)	0.003
Antimalarial use	60	68	0.039
Belimumab use	57	67	0.003

Survival analysis

The hazard ratio (HR) for the probability of renal failure was significantly increased following assessment of levels of C3 and all autoantibodies (Table 2).

Table 2. Biomarker analysis*

CI, confidence interval; ds, double-stranded; HR, hazard ratio; Sm, Smith. *Adapted from Gomez.1
Biomarker	HR	95% CI	p value
Low C3	2.9	2.1–4.1	<0.001
Low C4	1.2	0.9–1.6	0.147
Positive anti-dsDNA	2.1	1.4–3.2	<0.001
Positive anti-Sm	2.2	1.4–3.3	<0.001
Anti-ribosomal P	2.3	1.5–3.6	<0.001

Following adjustments (for age, sex, ethnicity, body mass index, SDI, Systemic Lupus Erythematosus Disease Activity Index 2000 score, previous renal involvement, use of glucocorticoids, use of antimalarial agents, immunosuppression, and belimumab), low C3 and high proteinuria remained significant (p < 0.01 and p < 0.001, respectively) for indicating renal flare along with low levels of plasma albumin.

Subgroup analyses

The biomarkers of interest were also analyzed in a subgroup of patients who had BILAG A-D scores available (n = 1,761). In this subgroup analysis, only low C3 levels were significantly associated with an increased HR for the risk of renal flares (Table 3).

Table 3. Subgroup analysis of biomarkers for renal flare in patients with BILAG A-D score*

CI, confidence interval; ds, double-stranded; HR, hazard ratio; Sm, Smith. *Adapted from Gomez.1
Biomarker	HR	95% CI	p value
Low C3	2.2	1.6−3.1	<0.001
Positive anti-dsDNA	1.4	0.9−2.1	0.126
Positive anti-Sm	1.7	1.1−2.6	0.022
Anti-ribosomal P	1.8	1.2−2.9	0.009

As belimumab is thought to improve low C3 and decrease anti-dsDNA, a subgroup analysis of patients treated with belimumab vs placebo was performed. In this analysis, the HR for baseline low C3 was 2.7 (range, 1.7−4.4) versus 3.3 (range, 2.1−5.0) in the belimumab arm. For positive presence of anti-dsDNA, the HR in the placebo group was 2.0 (1.2−3.5) compared with 2.3 (1.3−4.0). The investigators took these differences to be small enough to allow for the treatment arms to be examined together.

Conclusion 

In this post-hoc analysis of four trials, low C3, hypoalbuminemia, and high levels of proteinuria were associated with increased risk of renal flares. Low C3 was also significantly associated with an increased risk of renal flares in a subgroup analysis of patients with available BILAG A-D scores. The results of this analysis suggest that these laboratory markers may be suitable as biomarkers for renal flares.