EULAR 2023 recommendations for SLE treatment: synopsis for the management of lupus

nephritis – the European Renal Association (ERA) - Immunonephrology Working Group

(ERA-IWG) perspective

Eleni Frangou1, Annette Bruchfeld2,3, Gema M. Fernandez-Juarez4, Jürgen Floege5, Dimitrios

Goumenos6, Sarah M. Moran7, Stefanie Steiger8, Kate I Stevens9, Kultigin Turkmen10, Andreas
Kronbichler11*

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Department of Nephrology, Limassol General Hospital, Limassol, Cyprus; University of Nicosia
Medical School, Nicosia, Cyprus

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Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
3

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Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet,
Stockholm, Sweden

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4
Department of Nephrology, Hospital Unversitatio La Paz, Madrid, Spain. Instituto de Investigacion la
Paz. IDIPaZ.

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5
Division of Nephrology, RWTH Aachen University Hospital, Aachen, Germany

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6
Department of Nephrology and Renal Transplantation, Patras University Hospital, Patras, Greece
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Cork University Hospital, University College Cork, Cork, Ireland
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Renal Division, Department of Medicine IV, Ludwig-Maximilians-University Hospital Munich,
Ludwig-Maximilians-University Munich, Germany
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Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK
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Division of Nephrology, Department of Internal Medicine, Necmettin Erbakan University, Konya,
Turkey
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Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck,
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Innsbruck, Austria
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Correspondence to:
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Andreas Kronbichler; E-mail: andreas.kronbichler@i-med.ac.at, Twitter handle: @akronbichler

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© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
 In the 2023 update of the EULAR recommendations for the management of systemic lupus
erythematosus (SLE), the task force make three specific suggestions for the management of
lupus nephritis (LN) and place strong emphasis on the treatment of active LN [1]. This is
primarily a consequence of the recent approvals of belimumab, a monoclonal antibody
directed against the cytokine BLyS, and voclosporin, a novel calcineurin inhibitor, as add-on
therapies for the management of active LN. This Editorial specifically focuses on the key

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clinical trials (BLISS-LN [2] and AURORA-1 [3]) which form the basis for the updated EULAR
recommendations.
Efficacy of belimumab and voclosporin in the therapy of active LN

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In brief, belimumab and voclosporin were tested on top of standard-of-care therapy in the
BLISS-LN and AURORA-1 trials (see Table 1 for details) [2, 3]. The endpoint measurements
differed between both trials (Table 1) but the primary endpoint was reached by 43% in the

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belimumab arm in BLISS-LN at 104 weeks (versus 32% in the placebo arm) and 41% in the
voclosporin arm in AURORA-1 at 52 weeks (versus 23% in the placebo arm) [2, 3].

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Observational studies demonstrated that phases of active LN, encountered in 24% of study
visits, increase the likelihood to develop progressive kidney damage in over 50% of cases [4].

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Failure to achieve at least a partial renal response at 12 weeks predicted not only a higher

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Systemic Lupus International Collaborating Clinics/American College of Rheumatology
Damage Index (SDI) but also a higher cumulative glucocorticoid exposure over time [5]. To
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this end, the 2023 EULAR update of the recommendations state that the addition of either
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belimumab or voclosporin should be considered upfront [1], as the remission rates achieved
in clinical trials in control arms were low, and achieving no remission was associated with
damage accrual.
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Both belimumab and voclosporin are useful additions to the armamentarium to optimize LN
management. However, which of these two agents should be the preferred treatment
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choice for patients with LN (see considerations by this group in Figure 1)? The 2023 EULAR
update outlines differences in trial designs. Patients with an estimated glomerular filtration
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rate (eGFR) of < 45 ml/min per 1.73 m 2 were excluded from the AURORA-1 trial [1, 3]. Of
note, even in BLISS-LN most (83%) of the randomized patients had relatively “preserved”
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kidney function with an eGFR above 60 ml/min per 1.73 m2 and an average eGFR of 100.5
ml/min per 1.73 m2; thus, information on patients with lower eGFR categories is also limited
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for belimumab [2]. Yet logic dicatates that those with active LN irrespective of eGFR should
probably receive more “aggressive” therapies, in an endeavour to prevent further decline in
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eGFR.
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Long-term glucocorticoid exposure is common in patients with LN, either as part of the
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strategy to maintain remission in LN or to control extra-renal disease activity. Assuming

there are no contraindications, patients should be commenced on intravenous
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methylprednisolone (250-1,000 mg for 1-3 pulses) followed by a lower dose glucocorticoid

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regimen (starting dose 0.3-0-5 mg/kg/day and 20 mg/day for classes III-V). This
recommendation largely reflects the use of glucocorticoids in the AURORA-1 trial and the
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2023 EULAR update acknowledges the lack of high-quality data for this statement [1].
 Limited data is available in patients receiving belimumab, although a glucocorticoid-sparing
effect was proposed.
Although the 2023 EULAR update proposes that besides voclosporin, a second calcineurin
inhibitor, tacrolimus, can be used equivalently to manage active LN [1], there is no evidence
from high-quality clinical trials about tacrolimus efficacy outside of China [6]. The largest trial
included a total of 368 LN patients with a follow-up of six months. Patients in both groups
[intravenous cyclophosphamide versus low-dose tacrolimus (2 mg twice daily) plus low-dose

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MMF (500 mg twice daily)] received 3 doses of intravenous methylprednisolone (500 mg)
upfront, followed by an oral glucocorticoid dose of 0.6 mg/kg per day for 4 weeks and a slow
taper until 10 mg/day was reached. Thus, the total glucocorticoid exposure in the trial by Liu
et al. [7] is not comparable to more contemporary approaches in reducing the use of

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glucocorticoids, as also stated by the 2023 EULAR update [1].
In the pivotal tacrolimus trial, an astonishing number of 213 participants (57.9%) did not

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complete the 24 weeks of the trial [7]. Importantly, the side effect spectrum of voclosporin
and other calcineurin inhibitors, such as tacrolimus, is different, with voclosporin having

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lower frequencies of nephrotoxicity, neurotoxicity, dyslipidemia and de novo diabetes
mellitus [8]. Most of these estimates stem from kidney transplant recipients. It remains

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unclear whether these side effects are observed at the same frequency in patients with LN
receiving tacrolimus. Nonetheless, the ERA-IWG believes that, despite the potential cost

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reduction associated with tacrolimus compared with voclosporin, the recommendation for

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the use of tacrolimus is not currently supported by suffcient evidence, other than in a
Chinese population (see the Supplementary File for a current price estimate of both agents).
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Tacrolimus might, however, be considered in countries where voclosporin will not become
readily available (including in low income countries).
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How long should a patient be maintained on immunosuppression?

The ultimate goal of therapy is to prevent further episodes of active LN thus reducing the
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likelihood of progressive nephron loss. The 2023 EULAR update recommends that treatment
for LN should be continued for at least three years [1]. The BLISS-LN trial followed patients
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for 104 weeks, while recently published results from the AURORA-2 trial evaluated 216 of
the 357 patients that were originally randomized in the AURORA-1 trial for another 104
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weeks. Briefly, AURORA-2 found that the improved proteinuria response persisted up to
three years and, eventually led to more renal responses in patients receiving voclosporin. In
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AURORA-2, the corrected eGFR (all values higher >90 ml/min/1.73 m2 were constrained to
90 ml/min/1.73 m2) slope was -0.2 ml/min/1.73 m2 and -5.4 ml/min/1.73 m2 in the
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voclosporin and control groups, respectively [9]. This further demonstrates that
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nephrotoxicity over time seems to be only a minor issue for voclosporin.

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The 2023 EULAR update states that glucocorticoids should be withdrawn as soon as
sustained remission is achieved. The 10-year follow-up data from the EuroLupus Nephritis
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Trial reported the ongoing use of glucocorticoids in 73% of patients and alternative
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immunosuppressants in 56% in spite of good clinical renal outcome [10]. Based on these
real-life data of individuals receiving cyclophosphamide induction therapy, it seems relevant
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that glucocorticoids are tapered to the lowest possible dose early in the maintenance phase
 and ideally discontinued if extra-renal manifestations permit. The EULAR 2023 update
recommends a maintenance dose of ≤5 mg/day [1]. Observational data indicated that
glucocorticoid doses > 5 mg are associated with damage accrual in patients with SLE [11].
However, large registries of other autoimmune disorders, such as rheumatoid arthritis,
revealed that even lower doses (≥ 5 mg) and cumulative doses of over 0.75 g over the
preceding six months contribute to the risk to develop cardiovascular events [12], a finding
likely also of relevance for patients with LN, who have a high burden of cardiovascular

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morbidity and mortality.
The EULAR recommendations also note the potential value of repeated kidney biopsy to
guide reduction and withdrawal of immunosuppression, when patients are in remission for
at least two years [1]. In the case of limited/no evidence of histologic activity (NIH activity

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index (AI) of ≤1), it might be attempted to reduce or stop glucocorticoids, if such agents are
used to maintain remission. Other immunosuppressants might be reduced/withdrawn over
time. Evidence for such an approach is promising, although this has not been confirmed in a

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randomized controlled trial setting. Combining histological and certain clinical parameters,
e.g. degree of residual proteinuria, complement serology, antibody profile and adverse

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event occurrence or risk, might provide further insight to help guide withdrawal of
immunosuppression after three years of continuous therapy.

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Conclusion and future research agenda

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Although recent studies performed in LN patients have been critical of the suggested
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revisions, the 2023 update of the EULAR recommendations for the management of SLE is an
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important resource for physicians caring for patients with SLE and active LN.
The future research agenda mandates a strong focus on how to guide immunosuppression
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withdrawal and particularly notes the role of repeated kidney biopsy. Moreover, background
disease medication – e.g. steroid - has to be addressed in future trial design to avoid both
polypharmacy and “dilution” of positive effects of drugs under study [1]. A high-dose
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background therapy could have potentially led to the failure of rituximab therapy to achieve
significant results in the LUNAR trial with an efficacy difference of 11% compared to the
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control group [13].

The ambition to reduce effective background therapies to provide a positive signal seems to
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be a worrisome suggestion for future clinical trials. It should not be. Ideally, these newer
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therapies may provide similar or better efficacy estimates as currently approved therapies
and should provide such efficacy (and safety) on a standard background therapy.
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The use of sodium glucose co-transporter 2 (SGLT2) inhibitors as nephroprotective

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treatment is mentioned in the 2023 EULAR update; however, while preliminary data seem to
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be promising in patients with LN, a clinical trial focusing on nephroprotection is not

highlighted in the future research agenda [14]. The future for new drugs in the field of LN
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looks promising, and newer therapies such as anifrolumab, obinituzumab, and complement
inhibitors will further refine therapies and improve understanding disease pathogenesis in
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more detail. Additionally, the importance of biomarkers in detection of disease activity,

response to therapy and the early detection of non response should not be overlooked.
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 ACKNOWLEDGEMENTS
The Immunonephrology Working Group is an official body of the ERA.

FUNDING
This work received no funding.

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AUTHORS‘ CONTRIBUTIONS
AK drafted the first version of the article. All authors significantly contributed to the content and

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reviewed the manuscript.

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CONFLICT OF INTEREST STATEMENT

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AB received consultancy fees and honoraria from Amgen, AstraZeneca, Bayer, Fresenius, and CSL
Vifor. KIS received consultancy fees from Bayer and Boehringer Ingelheim. AK received consultancy

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fees from CSL Vifor, Otsuka, GSK, Walden Biosciences, Catalyst Biosciences, and Delta4; and received

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unrestricted research grants from CSL Vifor and Otsuka, GFJ received consultancy fees from GSK and
Otsuka. Remaining authors disclosed no conflicts of interest. A
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REFERENCES
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Lupus Nephritis. N Engl J Med 2020;383(12):1117-1128

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lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3

trial. Lancet 2021;397(10289):2070-2080
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5. Hanaoka H, Yamada H, Kiyokawa T, et al. Lack of partial renal response by 12 weeks after
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7. Liu Z, Zhang H, Xing C, et al. Multitarget therapy for induction treatment of lupus nephritis: a
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13. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active
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14. Caravaca-Fontán F, Stevens K, Padrón M, et al. Sodium-glucose cotransporter 2 inhibition in
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 Table 1. Differences among the two key trials leading to approval of belimumab (BLISS-LN) and
voclosporin (AURORA-1) in patients with active lupus nephritis (LN) classes III-V. In the results
section, the active group (belimumab or voclosporin) is always given first.

Trial BLISS-LN2 AURORA 13

Phase III III
Number of patients 448 357
Immunosuppression  EUROLUPUS CYC (6  MMF at a dose of 2 g/day
(background, induction) infusions CYC a fortnight (doses of up to 3 g/day

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apart) or MMF (target
dose 3 g/day)
 High-dose GCs (i.v. MP at
investigator’s discretion),
followed by oral
were permitted with
monitor approval)
 MP 0.5 g/day or 0.25
g/day based on body
weight (day 1 and 2), 20-

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prednisone (0.5-1.0 25 mg/day GC on day 3,
mg/kg/day, max. 60 decreased to 2.5 mg/day
mg/day), 25 mg/day at at week 16

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week 7 and 10 mg/day at
week 12

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Immunosuppression  AZA (2 mg/kg body  MMF
(background, maintenance) weight/day, max. 200  GCs: 2.5 mg/day (further
mg/day a day) or MMF (1- reduction at

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3 g/day) investigator’s discretion)
 GCs: max. 10 mg/day by

Active treatment arm
Comparator (placebo) arm
Lupus nephritis class
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week 24
Belimumab (10 mg/kg body Voclosporin 23.7 mg twice daily
weight) on days 1, 15, 29, and then
every 28 days to week 100)
A(6 tablets in total) for 52 weeks
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Placebo Placebo
III or IV: 56% versus 59% III or IV: 62% versus 59%
V: 16% versus 16% V: 14% versus 14%
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Mixed: 27% versus 25% Mixed: 24% versus 26%

Primary end point 96 (43%) versus 72 (32%)* 73 (41%) versus 40 (23%)*2
Complete renal response 67 (30%) versus 44 (20%) (see above, primary end point)
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Proteinuria at baseline (UPCR) 3.2±2.7 versus 3.5±3.6 4.1±2.7) versus 3.9±2.4)

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GFR at baseline (ml/min/1.73 100.0±37.7 versus 101.0±42.7 92.1± 30.6) versus 90.4± 29.0)
m2)
Δ GFR change (ml/min/1.73 Δ (approximately*1) +10 versus +/- Δ +1.0 versus 1.1 (at week 52)
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m2) from baseline 0 (at week 104)

Follow-up time (weeks) 104 52
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Serious adverse events 58 (26%) versus 67 (30%) 37 (21%) versus 38 (21%)

Serious infections/infestations 15 (7%) versus 18 (8%) 18 (10%) versus 20 (11%)
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Abbreviation: AZA (azathioprine), CYC (cyclophosphamide), GC (glucocorticoid), GFR (glomerular filtration

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rate), MMF (mycophenolate mofetil), MP (methylprednisolone), SD (standard deviation), UPCR (urinary

protein to creatinine)
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* Primary efficacy renal response (primary end point): UPCR of 0.7 or less, eGFR no worse than 20% below
the pre-flare value or at least 60 ml/min/1.73 m2, and no use of rescue therapy for treatment failure
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*1 Based on estimates given in Suppl. Figure 4 of the original manuscript

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*2 Primary end point (complete renal response): UPCR of 0.5 mg/mg or less, eGFR of 60 ml/min/1.73 m2
or more and no confirmed eGFR decrease of more than 20% from baseline
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 Figure 1. Specific considerations when evaluating the optimal currently approved add-on
therapy of a patient with active lupus nephritis (LN) class III-V.

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Abbreviations: BEL (belimumab), eGFR (estimated glomerular filtration rate), i.v.
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(intravenous), s.c. (subcutaneous), VCS (voclosporin).

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