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AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
In 1800s, Ferdinand von Hebra used the metaphor of a butterfly to describe the classic malar rash observed in systemic lupus erythematosus. But would he still considered the metaphor of a beautiful creature if all of the protean manifestations that the disease can present with was known then?! The incidence and prevalence of systemic lupus erythematosus (SLE) and lupus nephritis (LN) differ depending on the population studied and the diagnostic criteria used to identify SLE and LN; for example, whether LN is defined solely by clinical criteria or also by histological findings. An international inception cohort study found that among patients with SLE, the frequency of LN was higher for African, Hispanic, and Asian populations (39.9%, 49.3% respectively 36.8%), compared to white people (20.3%). Patients with nephritis tended to be younger, more often male, and of African, Asian, and Hispanic racial/ethnic origin. With nephritis, the estimated 10-year incidence of ESRD was 10.1%, and the estimated overall incidence was 4.3%. Patients with nephritis had a 3 times higher risk of death ). Hence what seems to be definite is each lupus nephritis (LN) flare results in significant nephron loss, making prompt initiation of therapy and flare avoidance critical. Thus, it is anticipated that identification of readily discernible approaching flare signals will enhance prognosis. Also will it not improve the overall quality of the patients if a “wonder” drug prevents the occurrence of ‘de novo’ flares?
According to a seminal study by Pollak et al, which was published in the early 1960s, proliferative LN improved after therapy with high-dose corticosteroids. As corticosteroids became the standard-of-care (SOC) for LN, patient survival rates for proliferative illness increased to 55% at five years. Then, in the 1980s, it was demonstrated that cytotoxic drugs may be added to corticosteroids to stop the progression of renal failure, and the inclusion of cyclophosphamide increased patient survival to 80% after five years. Since then, the standard of care in managing lupus nephritis has been in two phases: induction of remission and its maintenance, along with the use of antimalarials, statins, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. Despite the use of corticosteroids and other immunosuppressants such as cyclophosphamide, mycophenolate mofetil, azathioprine have increased patient survival they come with an important burden of drug toxicity.
Newer insights into the pathogenesis of lupus nephritis have led to the development of biologic targets. Based on the findings of the AURORA trials, the new oral calcineurin inhibitor voclosporin was authorized for LN in January 2021. The anti-interferon monoclonal antibody anifrolumab is the newest addition to the arsenal of SLE, which is currently under phase III trial.
Figure 1. depicting mechanisms and targets of newer treatments in lupus nephritis (created withBioRender.com)
Belimumab, a monoclonal antibody (mAb) against B cell activating factor (BAFF), was the first biological treatment for SLE to be authorized in 2011. Belimumab was subsequently approved for the treatment of LN in December 2020 following a landmark paper, BLISS-LN, by Richard Furie et al. Interestingly, there were observed instances of ‘de novo’ LN during Belimumab treatment. This brings us to the present study by Parodis et al, which evaluated the efficacy of belimumab in preventing de novo renal flares in patients undergoing standard therapy (ST) with or without add-on belimumab in a post hoc analysis of data from 5 phase 3 clinical trials. The authors also described the predictors of such ‘de novo’ renal flares in this population.
Study population:
The study population consisted of 1844 patients from 5 phase III clinical trials. Patients had no history of or current renal lupus involvement based on their baseline renal British Isles Lupus Assessment Group (BILAG) score of E, a baseline renal SLE Disease Activity Index 2000 (SLEDAI-2K) score of zero, and a urinary protein-to-creatinine ratio <0.5 mg/mg.
BLISS-52 (intravenous [IV] belimumab, NCT00424476, N= 865)
BLISS-76 (IV belimumab, NCT00410384, N=819)
BLISS-NEA (IV belimumab in Northeast Asia, NCT01345253, N=677)
BLISS-SC (SC belimumab, NCT01484496, N= 836)
EMBRACE (belimumab in patients with SLE who are of African ancestry, NCT0163224, N=448)
Inclusion criteria:
Adult patients fulfilling the American College of Rheumatology revised criteria for SLE
Antinuclear antibody titer ≥ 1:80 and/or serum antidsDNA antibody level ≥30 IU/ml at screening
Safety of Estrogens in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index score ≥ 6 (BLISS-52 and BLISS-76) or ≥8 (BLISS-SC, BLISS-NEA, or EMBRACE)
All patients were on stable nonbiological standard therapy (ST) for ≥30 days before the baseline of the double-blinded phase.
Exclusion criteria:
Severe active central nervous system involvement
Severe active LN
Intervention:
BLISS-52 & BLISS-76:
Patients received belimumab 1 mg/kg, belimumab 10 mg/kg, or placebo in addition to ST for 52 weeks and 76 weeks in BLISS-76.
Belimumab and placebo were administered IV at baseline, week 2, week 4, and thereafter every fourth week until week 48 in BLISS-52 and until week 72 in BLISS-76
BLISS-NEA and EMBRACE: Patients received belimumab 10 mg/ kg or placebo in addition to ST
BLISS-SC: Patients received weekly doses of belimumab 200 mg or placebo, administered SC in addition to ST
Flare Definition: Using the proposed definition of SLE flares measured by the BILAG index, de novo renal flare was defined as a change from renal BILAG E to a renal BILAG A or B within 52 weeks follow-up, as demonstrated below.
Serological markers used in prediction of flare:
anti-dsDNA positivity ≥30 IU/mL
anti-Smith (Sm) positivity ≥15.0 IU/mL
anti-ribonucleoprotein positivity ≥25 IU/mL
anti-ribosomal protein P positivity ≥12.0 IU/ mL in BLISS-52; ≥12.4 IU/mL in BLISS-76; ≥12.5 IU/mL in BLISS-SC
antiphospholipid positivity
anticardiolipin immunoglobulin (Ig)A ≥ 10.0 IU/mL in BLISS-52 and BLISS-76; ≥11.0 IU/mL in BLISS-NEA, BLISS-SC, and EMBRACE
anticardiolipin IgG ≥10.0 IU/mL in BLISS-52 and BLISS-76; ≥14.0 IU/mL in BLISS-NEA, BLISS-SC, and EMBRACE
anticardiolipin IgM ≥10.0 IU/mL in BLISS-52 and BLISS76; ≥12.0 IU/mL in BLISS-NEA, BLISS-SC, and EMBRACE
antiβ2-glycoprotein I (β2-GPI) IgA, IgG, and IgM ≥21.0 IU/mL for all Ig isotypes
Lupus anticoagulant positivity ≥45.0 IU/mL in BLISS-SC, ≥41.0 IU/mL in EMBRACE
low levels of C3 <90.0 mg/dL
low levels of C4 <16.0 mg/dL in BLISS-52 and BLISS-76; <10.0 mg/dL in BLISS-NEA, BLISSSC, and EMBRACE
Levels of B cell activating factor belonging to the tumor necrosis factor family
Results:
Of 1844 study participants with all trials combined, 602 received IV belimumab 10 mg/kg, 311 received IV belimumab 1 mg/kg, 343 received SC belimumab and 588 study participants received placebo.
A total of 136 patients (7.4%) developed at least 1 de novo renal flare during 52-week follow-up (13 patients with BILAG A; 123 patients with BILAG B). Among patients who developed flares, there was a greater proportion of Asian origin (31.6% in the flare group vs. 20.7% in the no-flare group; P = 0.004). With respect to serology, patients who presented with renal flare had positive anti-dsDNA levels at baseline (74.3% vs. 61.6%; P = 0.004) and/or low baseline levels of C3 (51.5% vs. 38.8%; P = 0.005) or C4 (47.1% vs. 36.4%; P = 0.017) compared with patients who did not develop renal SLE. Among other things, male sex was associated with a lower risk of de novo renal flares (HR: 0.49; 95% CI: 0.27-0.92; P = 0.025).
Individuals who received IV belimumab 1 mg/kg (non-licensed dose) had a lower proportion of de novo renal flares (13/311; 4.2%) than placebo-treated patients (26/300; 8.7%; P = 0.036). The proportion of patients who developed de novo renal flares after receiving IV belimumab 10 mg/kg (licensed dose; 48/602, 8.0% vs. 45/419, 10.7%; P = 0.161) or SC belimumab 200 mg (licensed dose; 18/343, 5.2% vs. 12/169, 7.1%; P = 0.523) did not differ from the proportion of placebo-treated patients in the same studies. Hence, despite indicating a benefit, the association between IV belimumab 10 mg/kg and the occurrence of de novo renal flare did not achieve statistical significance (HR: 0.74; 95% CI: 0.49-1.11; P = 0.143).
Following literature evidence of ‘de novo’ cases of LN arising during belimumab treatment, an attempt to identify the frequency and predictors of ‘de novo’ renal flare in patients receiving belimumab or placebo in addition to non-biological standard therapy (such as antimalarials, immunosuppressants, and glucocorticoids) was done.
Figure 2 Belimumab dosage forms in relation to development of at least 1 renal flare. (a) IV belimumab 1 mg/kg, (b) IV belimumab 10 mg/kg, or (c) SC belimumab 200 mg, and placebo-recipients from Parodis et al, KI Reports, 2023
Important predictors of renal flares were presence of positive anti-dsDNA and anticardiolipin (IgA and IgG) antibodies.
The current study suggests that low-dose belimumab protects against de novo LN flares. The authors propose that lower belimumab dosages than those currently licensed justify further investigation for the treatment of patients with SLE and low-grade or no proteinuria. Parodis et al, hypothesized that de novo LN cases treated with belimumab may occur, which is based on the assumption that LN activation might result from belimumab's inhibition of regulatory B cell subsets. This theory is backed by their earlier discovery that serum interleukin-10 drops quickly, noticeably, and persistently upon beginning belimumab treatment. The primary functions of IL-10 were initially associated with the suppression of cytokine secretion and termination of inflammatory responses. However, there is evidence that IL-10 may induce and amplify the production of autoantibodies in autoimmune conditions. As a result, IL-10 levels may reflect the inflammatory state in such conditions. With this in mind, it is surprising that belimumab as a supplement to standard LN therapy demonstrated favorable renal outcomes in the BLISS-LN trial. Recall, however, that the present study was conducted in a very different population; SLE patients without renal involvement. In this regard, conclusions from a trial of IV belimumab 120 mg that is now being conducted in China are expected to shed further light on our understanding.
The post-hoc nature of the current investigation, as well as the selection bias imposed by the trial criteria, limit the application of findings to real-world populations. Furthermore, renal flares were not detected using a kidney biopsy. Nonetheless, the authors believe that this is the largest study to date looking into the protection provided by belimumab against de novo renal flares in a nonrenal SLE group.
Before conclusion, let’s recap the main ideas, looking at this beautiful visual abstract, made by @DrPSVali
In conclusion, patients of Asian descent appeared to be particularly vulnerable to new onset renal involvement. In individuals with SLE who had no past history of nephritis, adding low-dose IV 1 mg/kg and SC 200 mg belimumab in addition to nonbiological ST appeared protective against renal flares, whereas adding the permitted IV dose (10 mg/kg) produced no obvious protection. It is crucial to note that the approved IV belimumab dose did not appear to predispose to renal flare, providing reassurance.
This study leaves with potential research questions.
Why are there inconsistent outcomes between low and recommended IV belimumab dosages?
Do the belimumab inhibitory effects on B cell subsets with regulatory features increase risk of de novo flares?
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.