Executive Summary of the 2024 Asia-Pacific League of Associations for Rheumatology Consensus Statements on Lupus Nephritis Management

Lupus nephritis (LN) is more prevalent and severe in Asian than Caucasian patients with systemic lupus erythematosus (SLE), which is related to the disparities in genetic background, health care access, adherence and tolerability to therapeutic regimens [1]. The Asia-Pacific League of Associations for Rheumatology (APLAR) published a consensus on the management of SLE in 2021 [2]. Since its publication, two novel agents, namely belimumab and voclosporin, have been approved for LN, leading to their incorporation in the 2024 KDIGO LN guideline and the 2023 EULAR recommendations for SLE [3, 4]. The APLAR SLE special interest group conducted two rounds of Delphi exercise to update the 2021 consensus [2], with a special focus on LN, after reviewing the latest literature. The level of evidence (A-D) and the strength of recommendation (A/B) were graded for each statement. A total of 31 rheumatologists, 13 nephrologists, 2 renal histopathologists and 2 LN patients from 21 Asia-Pacific regions were involved and 48 statements were agreed upon, with a consensus level of ≥ 80%. This executive summary provides an overview of the consensus, and please refer to the full paper published in this issue of International Journal of Rheumatic Diseases for the results of literature review and Delphi discussions.

The first section of the APLAR consensus statements on LN management states the overarching principles. Management of LN requires a shared decision between patients and physicians, considering the availability of healthcare resources across the APLAR region. The goals of treatment and the importance of adherence are underscored. LN should be monitored by clinical and laboratory parameters (urine protein and SLE activity markers) and additional tests (e.g., urine sediments) when a flare is suspected. The indications of kidney biopsy to assess for the histologic class, activity and chronicity, and additional features such as podocytopathy, microangiopathy and interstitial inflammation, are suggested.

Recommendations on initial and subsequent therapies of LN are the major parts of the APLAR consensus (sections 3–7). Immunosuppressive therapies are indicated in histologically active class III/IV ± V, pure class V (with significant proteinuria) or class I/II (with significant podocytopathy or nephrotic range of proteinuria) LN. When kidney biopsy is not feasible, immunosuppressive therapies should be individualized based solely on clinical parameters. The first-line treatment for active proliferative (class III/IV ± V) LN is a combination of moderate doses of glucocorticoids (GCs) (0.6 mg/kg/day of oral prednisolone or equivalent) with (1) mycophenolic acid analogues (MPAA) (mycophenolate mofetil [MMF] or mycophenolic acid [MPA]); (2) standard-dose intravenous (IV) cyclophosphamide (CYC) or (3) calcineurin inhibitor (CNI). Unlike the 2024 KDIGO [3] and the 2023 EULAR recommendations [4], we continue to recommend the standard dose instead of the reduced-dose IV CYC regimen because Asian patients tend to have more serious LN. The reduced-dose CYC regimen is reserved as a second-line option, especially in patients at risk of infective complications but without poor prognostic factors. The combination of GC and CNI (especially tacrolimus) is now recommended as one of the first-line options from new evidence in Chinese patients showing non-inferiority of tacrolimus to CYC [5].

There was discussion about the upfront combination of GC, MPAA or CYC with the CNI or biological agents. Two recent phase III RCTs demonstrated additional benefit of addition of voclosporin, a newer generation CNI, or belimumab to standard therapy (GC plus MMF or CYC) [6, 7]. Owing to the cost-effectiveness issue and the level of evidence in the Asian subgroup, we recommend this approach for LN patients at risk of disease progression (section 7), in contrast to the 2021 version of the APLAR SLE recommendation in which triple immunosuppression was only suggested as add-on therapy for refractory disease [2]. Treatment options for high-risk patients include standard-dose IV CYC, triple therapy (GC, MPAA and CNI) and combining belimumab with standard regimens. Switching among regimens (CYC, MMF, CNI), or the addition of the biological agents (belimumab or rituximab) could be considered for patients with suboptimal response to one therapeutic regimen. Although voclosporin is not yet available in most Asia-Pacific countries, considerable experience of cyclosporine and tacrolimus in LN is available in Asian patients [5, 8-10]. For the treatment of pure class V LN, we suggest early use of renin-angiotensin system (RAS) blockers. First-line immunosuppressive therapies are GCs combined with either MPAA or CNI. Alternative options include azathioprine (AZA), CYC or low-dose combination of MMF and tacrolimus.

Maintenance therapy of LN (by MPAA or AZA) should follow induction regimens when the target response is achieved and continue for ≥ 3 years. The maintenance period may be prolonged in patients at risk of relapse. Patients who receive initial biological therapy may continue treatment depending on clinical response and residual disease activity. Low-dose prednisolone (≤ 5 mg/day) may be continued, and the decision to discontinue GCs and the tempo for tapering should be individualized.

Adjunctive therapies and management of LN-related co-morbidities are included in section 8. These include the universal use of hydroxychloroquine in all SLE patients, lifestyle modification, RAS blockade, anticoagulation, control of cardiovascular risk factors, and prevention of osteoporosis, drug-related toxicities and infective complications. The final section (section 9) of the consensus provides guidance on renal replacement therapies, use of immunosuppressive agents during dialysis, as well as the optimal timing for kidney transplantation. We hope that the 2024 APLAR consensus on the management of LN provides a pragmatic guidance for physicians who are engaged in the treatment of LN in this region of the world.

All authors have contributed equally to this summary and participated in the core group discussion of this consensus.

Chi Chiu Mok: none. Ho So: none. Laniyati Hamijoyo: none. Nuntana Kasitanon: none. Der Yuan Chen: none. Sang-Cheol Bae: none. Meng Tao Li: none. Sandra Navarra: consultation fee and speaker honorarium from Astra Zeneca and Boehringer Ingelheim; safety monitoring board for Biogen. Desmond Yat Hin Yap: financial support from Fresenius Kabi for conference attendance. Yoshiya Tanaka: grants from Behringer-Ingelheim, Taisho, Chugai; speaker honoraria from Abbvie, Eisai, Chugai, Eli-Lilly, Behringer-Ingelheim, Glaxo Smith Kline, Taisho, Astra Zeneca, Daiichi-Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, Astellas.