Lupus Nephritis · 2026 Update

From Biopsy to Biologics

狼瘡性腎炎的治療趨勢、腎臟切片的角色，與 Benlysta 實務經驗

腎臟科　紀竣議 醫師 臺大醫院雲林分院　National Taiwan University Hospital, Yunlin Branch
2026

Disclosures

Disclosures

Disclosures NTUH Yunlin Branch · Nephrology

Outline

大綱

01 Where LN stands in 2026 Outcomes, targets, ACR 2024 與 EULAR 2025
02 The kidney biopsy Indications, classification, activity/chronicity, repeat biopsy
03 Treatment trends Triple therapy, CNI, anti-CD20, pipeline, belimumab evidence
04 Case sharing 兩例接受 belimumab 的 LN 病人與追蹤結果
Outline 40 min

01 · Where LN stands

Lupus Nephritis: Scale of the Problem

40–60% of patients with SLE develop kidney involvement
10–30% of LN progress to kidney failure within 15 years
6 mo window in which response predicts long-term kidney survival
Epidemiology · UpToDate® 04

01 · Where LN stands

The Unmet Need Behind Standard of Care

  • —Complete renal response with dual therapy stays below 25% at one year; adding a third agent raises it to ~41%.
  • —Relapse after remission remains common and each flare adds chronic damage.
  • —Cumulative glucocorticoid exposure drives infection, bone loss and metabolic damage.
  • —Delay between clinical suspicion and definitive therapy is still measured in months.
CRR AT WEEK 52 · AURORA 1
Dual immunosuppression
~23%
Triple immunosuppression
~41%
AURORA 1 primary endpoint: voclosporin + MMF + low-dose steroid vs placebo + MMF + low-dose steroid.
Unmet need 05

01 · Where LN stands

Treatment Targets and Milestones

MONTH 3 ≥25% drop in proteinuria Normalising complement and anti-dsDNA
MONTH 6 ≥50% drop in proteinuria Prednisone tapered to ≤5 mg/day
MONTH 12 Proteinuria <0.7 g/g Stable or improving eGFR
YEAR 3+ Sustained complete response Before any withdrawal of therapy

Missing a milestone is an indication to escalate — not to wait for the next visit.

EULAR 2025 update · Ann Rheum Dis 2026;85:75–90 06

01 · Where LN stands

Two Guidelines, One Direction

ACR 2024
  • —Prompt kidney biopsy whenever LN is suspected (good practice statement).
  • —Triple immunosuppression proposed as the most desirable regimen.
  • —Prednisone ≤5 mg/day by month 6; total therapy 3–5 years.
  • —28 graded recommendations, 13 good practice statements.
EULAR 2025
  • —"Lupus nephritis" replaced by "SLE with kidney involvement".
  • —Early biopsy and early combination therapy, especially with adverse renal factors.
  • —Belimumab, obinutuzumab and rituximab all named among biologic options.
  • —Immune therapy ≥3 years after complete response; aggressive steroid withdrawal.
COMMON GROUND Biopsy early, combine early, taper steroids hard, treat long.
ACR 2024 guideline summary · EULAR 2025 update 07

Section 02

The Kidney Biopsy

切片決定分型、決定治療強度、決定預後判讀 — 也是腎臟科在 LN 照護中的核心貢獻

02 · Kidney biopsy

Why Histology Still Decides Therapy

Class assignment Proliferative disease and pure class V take different regimens; only histology separates them.
Activity vs chronicity Distinguishes treatable inflammation from established scarring — the difference between escalating and protecting.
Alternative diagnoses Thrombotic microangiopathy, podocytopathy, diabetic or drug-induced injury, vascular disease.
Reimbursement 健保 belimumab 給付以第 III、IV 或 V 型為前提 — 沒有病理，就沒有申請的起點。
Kidney biopsy · rationale 09

02 · Kidney biopsy

Biopsy Indications Are Widening

Screening Quantify proteinuria at least every 6–12 months in SLE, and at every extra-renal flare.
Threshold Proteinuria >0.5 g/g, or unexplained impaired kidney function — biopsy conditionally recommended.
Low-grade Proteinuria <0.5–1.0 g/day or isolated glomerular haematuria does not exclude histologically active disease.
Do not delay Start glucocorticoids for suspected LN while awaiting the biopsy and the report.
Practical Platelet count, blood pressure and anticoagulation planning decide the day, not the decision.
ACR 2024 · EULAR 2025 SLR 10

02 · Kidney biopsy

ISN/RPS Classification

I / II Minimal mesangial / mesangial proliferative — usually no immunosuppression for the kidney
III Focal (<50% glomeruli) — active (A), chronic (C), or mixed
IV Diffuse (≥50%) — the classic indication for intensive combination therapy
V Membranous — may be pure or combined with III/IV; nephrotic-range proteinuria
VI Advanced sclerosing (≥90% globally sclerosed) — CKD care, not immunosuppression
WHAT EACH MODALITY ADDS
LM — class, activity and chronicity IF — full-house staining, subepithelial deposits EM — subepithelial deposits, tubuloreticular inclusions
The three modalities together define class and guide therapy.
Report should always state class, plus activity and chronicity indices.
ISN/RPS 2003, revised 2018 consensus 11

02 · Kidney biopsy

Activity and Chronicity Index

ACTIVITY · 0–24 Endocapillary hypercellularity, neutrophils/karyorrhexis, fibrinoid necrosis, hyaline deposits, cellular crescents, interstitial inflammation Higher activity supports early combination immunosuppression.
CHRONICITY · 0–12 Global/segmental glomerulosclerosis, fibrous crescents, tubular atrophy, interstitial fibrosis Higher chronicity predicts kidney failure and limits what any regimen can recover.

Two patients with the same class IV label and opposite chronicity indices are not the same patient — and should not receive the same plan.

Modified NIH activity / chronicity index 12

02 · Kidney biopsy

Clinical and Histologic Response Diverge

IMPLICATION Treat the biopsy as a repeatable measurement, not a one-time entry ticket.
Clinico-pathologic discordance 13

02 · Kidney biopsy

When to Repeat the Biopsy

SUSPECTED FLARE Rising proteinuria, new haematuria, or falling eGFR after remission
NON-RESPONSE ≥6 months of appropriate therapy with ongoing or worsening kidney findings
BEFORE WITHDRAWAL Investigational, but increasingly used to justify tapering immune therapy

A repeat biopsy answers a question a laboratory panel cannot: is this active disease, or is it scar?

ACR 2024 · conditional recommendation 14

02 · Kidney biopsy

Adequacy Decides How Much the Report Is Worth

  • —Class assignment depends on the proportion of involved glomeruli; too few glomeruli can turn diffuse disease into a "focal" report.
  • —Light microscopy alone is insufficient — immunofluorescence and electron microscopy are needed for subepithelial deposits and full-house staining.
  • —Prior pulse steroids modify histology; note the treatment already given when reading the report.
  • —An under-sampled biopsy is a reason for a low threshold to repeat, not a reason to abandon histologic guidance.
FROM OUR OWN PRACTICE "Compatible with treated focal lupus nephritis with subepithelial deposit and inadequate glomerular amount (5 glomeruli)." Case 1 · biopsy after two days of pulse methylprednisolone — the report we later had to interpret against a nephrotic course.
Biopsy adequacy 15

Section 03

Treatment Trends

三個方向：早期組合治療、類固醇最小化、以病理與腎功能長期保存為終點

03 · Treatment trends

Triple Therapy as the Starting Point

PREVIOUS PRACTICE
Glucocorticoid + one agent MMF or low-dose CYC; escalate only after failure at 6–12 months
ACR 2024
Glucocorticoid + two non-steroid agents MPAA + belimumab · MPAA + CNI · ELNT low-dose CYC + belimumab
ACR 2024 guideline summary 17

03 · Treatment trends

Choosing the Third Agent in Class III/IV

CLINICAL FEATURE PREFERRED REGIMEN RATIONALE
Significant extra-renal disease MPAA + belimumab Systemic activity control and flare reduction
Proteinuria ≥3 g/g MPAA + CNI Faster antiproteinuric effect via podocyte stabilisation
Severe proliferative disease, crescents ELNT low-dose CYC + belimumab Rapid induction, then switch CYC to MPAA
Inadequate response by 6–12 months Alternative triple regimen or add anti-CD20 Check adherence and dosing first
Refractory after two courses MPAA + belimumab + CNI, or trial referral Weigh infection risk explicitly with the patient
ACR 2024 · conditional recommendations 18

03 · Treatment trends

Pure Class V: Proteinuria Sets the Intensity

PROTEINURIA ≥1 g/g Triple therapy: pulse steroid, taper, MPAA + CNI CNI adds a direct antiproteinuric effect on the podocyte.
PROTEINURIA <1 g/g Glucocorticoid and/or a single agent MPAA, AZA or CNI, with full non-immunologic kidney protection.
ACR 2024 · pure class V 19

03 · Treatment trends

Glucocorticoid Minimization

INDUCTION 250–1000 mg IV methylprednisolone daily for 1–3 days
ORAL START ≤0.5 mg/kg/day Maximum 40 mg/day, then structured taper
BY MONTH 6 ≤5 mg/day EULAR 2025 goes further: withdrawal where feasible

Steroid-sparing is not a secondary benefit of adding a biologic — for many patients it is the primary one.

ACR 2024 · EULAR 2025 20

03 · Treatment trends

Calcineurin Inhibitors and Voclosporin

  • —AURORA 1 and its 2-year extension established voclosporin plus MMF and low-dose steroid as an effective triple regimen.
  • —The antiproteinuric effect appears early — attractive for nephrotic presentations.
  • —Expect an initial eGFR dip; blood pressure and drug level monitoring are part of the regimen.
  • —Guidelines do not specify which CNI — availability and cost decide. Tacrolimus is the practical option in Taiwan.
  • —Long-term nephrotoxicity remains the open question, and argues against indefinite use.
WHEN CNI FITS BEST
Heavy proteinuria ≥3 g/g Pure or mixed class V Need for rapid proteinuria reduction Preserved baseline eGFR
Reassess continuation once complete response is sustained.
AURORA program · guideline commentary 21

03 · Treatment trends

Anti-CD20: What REGENCY Changed

COMPLETE RENAL RESPONSE · WEEK 76
Obinutuzumab + MMF + steroid
46.4%
Placebo + MMF + steroid
33.1%
Phase 3 REGENCY, class III/IV LN, N=271.
  • —First B-cell depleting agent with a positive phase 3 result in LN; FDA approval followed in late 2025.
  • —ACR 2024 already positions anti-CD20 for inadequate response or refractory disease.
  • —EULAR 2025 names obinutuzumab alongside belimumab and rituximab as a biologic option.
  • —Hypogammaglobulinaemia and infection surveillance become part of long-term follow-up.
  • —In Taiwan, access remains the limiting factor rather than evidence.
REGENCY (NEJM 2025) · figures for orientation 22

03 · Treatment trends

Four Mechanistic Routes in the Pipeline

B-CELL TARGETING BAFF, CD20, CD19, BAFF-R Belimumab, obinutuzumab, ianalumab, telitacicept; deeper depletion with more infection risk
INTERFERON PATHWAY Type I IFN receptor blockade Anifrolumab — phase 2 primary endpoint not met; phase 3 (IRIS) ongoing
COMPLEMENT Alternative pathway inhibition Factor B and related targets, borrowed from other glomerular diseases
IMMUNE RESET CD19 CAR-T and bispecific engagers Drug-free remission reported in small refractory series; trials only
Pipeline overview · investigational 23

03 · Treatment trends

Duration of Therapy and Withdrawal

3–5 years Total immunosuppressive therapy after complete renal response (ACR 2024)
≥3 years Immune and biologic therapy continued after complete response (EULAR 2025)
Indefinite Hydroxychloroquine and kidney protection, unless contraindicated
ACR 2024 · EULAR 2025 24

Section 04

Belimumab in Practice

BLISS-LN、亞洲與日本真實世界資料、14 年安全性，以及台灣健保實務

04 · Belimumab

BLISS-LN: Design

Population 448 adults with biopsy-proven active class III, IV or V lupus nephritis
Regimen Belimumab 10 mg/kg IV or placebo, added to standard therapy (MMF, or CYC followed by AZA)
Duration 104 weeks — the longest randomised LN trial to date
Primary endpoint PERR at week 104: UPCR ≤0.7 g/g, eGFR ≥60 or within 20% of pre-flare, no rescue therapy
Key secondary CRR (UPCR <0.5 g/g, eGFR ≥90 or within 10%), and time to kidney-related event or death
Furie R, et al. N Engl J Med 2020;383:1117–28 26

04 · Belimumab

BLISS-LN: Results at Week 104

PRIMARY EFFICACY RENAL RESPONSE
Belimumab + SoC
43%
Placebo + SoC
32%
COMPLETE RENAL RESPONSE
Belimumab + SoC
30%
Placebo + SoC
20%
KIDNEY-RELATED EVENT OR DEATH HR 0.51 Roughly half the risk over two years — the outcome that matters most to a nephrologist.
Furie R, et al. N Engl J Med 2020;383:1117–28 27

04 · Belimumab

Who Responds: Post-hoc and Registry Signals

  • —BeRLiSS-LN: 91 of 466 SLE patients on belimumab had renal involvement; 70.3% achieved PERR (proteinuria ≤0.7 g/g, eGFR ≥60).
  • —Higher baseline proteinuria, higher creatinine and hypertension predicted a lower chance of response — an argument for adding belimumab before damage accrues.
  • —86.7% of patients already in PERR at month 6 maintained the response through follow-up.
  • —Anti-Sm positivity and an early 6-month response predicted durable PERR at 12 and 24 months.
RESPONSE DEFINITIONS
CRR Proteinuria <0.5 g/24h · eGFR ≥90 mL/min/1.73m² · no rescue therapy
PERR Proteinuria ≤0.7 g/24h · eGFR ≥60 mL/min/1.73m² · no rescue therapy
Gatto M, et al. J Autoimmun 2021;124:102729 28

04 · Belimumab

East Asian Patients in BLISS-LN

  • —Pre-specified subgroup analysis of East Asian participants: renal response favoured belimumab, consistent with the overall population.
  • —No new safety signals; infection rates comparable to placebo plus standard of care.
  • —Relevant because East Asian cohorts carry more proliferative disease and higher baseline proteinuria.
  • —Subgroup sizes are small — treat the direction as supportive rather than definitive.
EAST ASIA SUBGROUP · BLISS-LN
  • —Earlier and more sustained improvement in kidney outcomes with belimumab than with placebo
  • —Directionally consistent with the overall BLISS-LN population
  • —No new safety signals
Prespecified subgroup — treat the direction as supportive, not definitive.
Yu X, et al. Am J Kidney Dis 2023;81(3):294–306 29

04 · Belimumab

Japan LOOPS Registry: Timing Matters

CONCLUSION Belimumab added to standard of care controlled disease activity, reduced glucocorticoid use and suppressed organ damage in proliferative lupus nephritis. Earlier induction within 6 weeks may help treatment-resistant patients achieve complete renal response.
Sakai H, et al. Rheumatology 2025;64(4):1930–1939 30

04 · Belimumab

Safety Across 14 Years of Exposure

2009–2011 Phase II and BLISS-52/-76 (N=449; N=1,684)
2017–2021 BLISS-SC and BASE (N=836; N=4,003)
2020–2022 EMBRACE and BLISS-LN (N=503; N=448)
2019–2023 PLUTO paediatric data and real-world exposure (N=93)
Consistent profile Safety findings in LN and paediatric populations were consistent with the known adult SLE profile; injection site reactions were added with the SC formulation.
What to monitor Serious infection, infusion and hypersensitivity reactions, and depression or suicidality — reported in the trial programme and to be discussed with patients.
Pooled trial and post-marketing safety data · see full prescribing information 31

04 · Belimumab

IV Dosing for Lupus Nephritis

DAY 0 10 mg/kg First infusion
DAY 14 10 mg/kg Second infusion
DAY 28 10 mg/kg Third infusion
THEN EVERY 4 WEEKS Maintenance Alongside standard therapy
Refer to TFDA-approved prescribing information 32

04 · Belimumab

健保給付條件與國際指引的落差

台灣健保規範 接受標準治療至少 6 個月但仍然無法有效控制疾病的第 III、IV 或 V 型狼瘡腎炎成人病人，且需經事前審查核准後使用。 前提：腎臟切片病理分型 ＋ 6 個月標準治療紀錄
GUIDELINE POSITION
  • —ACR 2024 places belimumab in first-line triple therapy, not after failure.
  • —Registry data suggest earlier induction improves the chance of complete response.
  • —Practical consequence: document the biopsy, the regimen and the response trajectory from day one, so the application is ready at month six.
健保給付規定 · 請以最新公告版本為準 33

Section 05

Case Sharing

兩位在雲林分院接受 belimumab 的狼瘡性腎炎病人

05 · Case 1

Case 1: Presentation

  • —49-year-old Japanese female, referred from endocrinology on 2022/06/08.
  • —Chief complaint: leg edema for three weeks.
  • —Hypothyroidism on supplementation; anemia of unknown cause; blood pressure 130/90 mmHg.
  • —Serology screen for glomerulonephritis sent (ANCA, anti-GBM, ANA, dsDNA, ENA, C3/C4, ASLO, sFLC ratio); admission arranged for kidney biopsy.
BASELINE LABORATORY
Creatinine0.6 mg/dL (eGFR 112.9)
Albumin1.5 g/dL
Hemoglobin10.7 g/dL
UACR>3,820 mg/g, dysmorphic RBC
NTUH Yunlin Branch · Nephrology 35

05 · Case 1

Case 1: Diagnosis and Kidney Biopsy

06/10Dyspnea; sent to the ED. Anti-dsDNA 30 IU/mL, anti-ENA positive, C3/C4 70.7 / 8.7, platelets 38 k/μL, hsCRP 8.39 mg/dL.
DIAGNOSISSLE flare with LN and nephrotic syndrome. HCQ, methylprednisolone 20 mg Q8H, PPI, co-trimoxazole, albumin support.
06/12–16Admitted with rheumatology; pulse methylprednisolone 500 mg 06/14–15, biopsy 06/16.
PATHOLOGY Compatible with treated focal lupus nephritis with subepithelial deposit; inadequate glomerular amount (5 glomeruli).
READING THIS REPORT
  • —5 glomeruli after two days of pulse steroids — "focal" may reflect sampling, not biology
  • —Subepithelial deposits point to class V overlap even with a low glomerular count
  • —Nephrotic course with positive serology → treat as proliferative LN
Low threshold to repeat the biopsy if the course diverges.
Case 1 · 2022/06 36

05 · Case 1

Case 1: Course to Complete Renal Response

4.11
22/08
2.77
22/09
1.06
22/10
1.50
22/12
1.39
23/02
0.83
23/04
0.51
23/12
0.23
24/04
0.13
24/09
UPCR (g/g)Six monthly CYC pulses plus AZA left UPCR at 1.39 with albumin 3.1.
2023/02 · BELIMUMAB APPLIED400 mg IV at days 0, 14, 28, then Q4W; prednisolone tapered to 1 tablet, AZA halved.
OUTCOMEAlbumin 3.8 g/dL, CRP normal, complete renal response after two years of therapy.
Case 1 · 2022/08–2024/09 37

05 · Case 2

Case 2: Class IV + V, a Slower Response

PRESENTATION
  • —25-year-old female, referred for foamy urine; weight up from 54 to 60 kg, BP 132/93.
  • —UPCR 8.70 at referral, 5.07 two weeks later; albumin 2.8 g/dL.
  • —ANA 1:1280, anti-dsDNA positive, anti-ENA positive, C3/C4 63.7 / 8.2.
  • —Biopsy 2023/03/08: diffuse and membranous lupus nephritis, class IV + V.
COURSE
2023/03Pulse methylprednisolone ×3, then PDN + MMF 2 g/day
2023/06UPCR 0.47 — best response on dual therapy
2023/08–10UPCR rebounds to 1.24 then 0.81 despite full MMF
2023/12UPCR 1.46 — belimumab 600 mg IV D0/D14/D28, then Q4W
2024/03–09COVID-19, cough and UTI episodes; steroid reduced to 1 tablet
2024/10UPCR 1.55, albumin 3.6 — partial response only; MMF switched to AZA

Mixed class IV+V with heavy proteinuria is the setting where guidelines now favour adding a CNI — a reasonable next step in this patient.

Case 2 38

Take home

Take Home Messages

01 Biopsy early, and repeat when the course does not match the report. Class, activity and chronicity decide intensity — and open the door to reimbursement.
02 Manage to milestones, not to visits. 25% at 3 months, 50% at 6 months, <0.7 g/g at 12 months; steroids ≤5 mg by month 6.
03 Triple therapy is the default, and belimumab is one of the three named options. BLISS-LN: belimumab plus standard therapy beats standard therapy alone, including kidney-related events.
04 健保規範與治療趨勢之間的差距，要靠完整紀錄來縮短。 腎臟切片 ＋ 6 個月標準治療紀錄，讓需要的病人在第六個月就能提出申請。
Take home messages 39

Thank you

Q & A

腎臟科　紀竣議 醫師 臺大醫院雲林分院　National Taiwan University Hospital, Yunlin Branch