2025+EULAR建议：累及肾脏的系统性红斑狼疮的管理（更新版）
A R T I C L E I N F O
Article history:
Received 24 June 2025
Received in revised form 11 September 2025
Accepted 15 September 2025
A B S T R A C T
Objectives: The objective of this study was to update the 2019 European Alliance of Associations for Rheumatology(EULAR)/ European Renal Association/European Dialysis Transplantation Association(ERA-EDTA) recommendations for the management of systemic lupus erythemato-sus(SLE) with kidney involvement, taking into consideration emerging evidence and recent developments in the field.
Methods: We recruited an International Task Force of experts and followed the EULAR standard operating procedures. We performed systematic literature research(period January 2019 to March 2024), followed by the modified Delphi method, to form questions, elicit expert opinions,and reach consensus. The new evidence was examined, taking into consideration previous updates.
Results: The Task Force agreed on 4 overarching principles and 13 recommendations, which were also evaluated for their feasibility and impact on clinical care. These concern the use of kid-ney biopsy for diagnosis; targets of therapy and treatment milestones; immunomodulatory ther-apy with antimalarials, glucocorticoids, immunosuppressives(mycophenolate,cyclophosphamide, and calcineurin inhibitors), and biologics(belimumab, obinutuzumab, and rituximab); nonimmune therapy(kidney protection, vaccinations, cardiovascular, and bone pro-tection); family planning; and management of kidney failure. Guidance on single-agent or early combination immune therapy, glucocorticoid tapering and withdrawal, duration of immune therapy, and treatment of refractory disease is provided.
Conclusions: The updated EULAR recommendations provide evidence- and expert-based consen-sus on the management of SLE with kidney involvement, adjusted for severity, and taking into consideration long-term efficacy, safety, cost, and local availability of drugs.
INTRODUCTION
Kidney involvement affects a significant proportion(20%-60%, depending on racial/ethnic background) of patients with systemic lupus erythematosus(SLE) and has a profound impact on prognosis[1]. Despite therapeutic advances, up to 15% of patients still reach kidney failure[2]. Moreover, 40% to 60% of patients with lupus nephritis(LN) develop chronic kidney dis-ease(CKD), associated with substantial morbidity, especially cardiovascular.
The European Alliance of Associations for Rheumatology(EULAR), in conjunction with the European Renal Association/European Dialysis Transplantation Association(ERA/EDTA),has published recommendations for the management of LN in 2012[3], which were updated in 2019[4]. Recently, a EULAR update of the management recommendations for general SLE was published, which included individual statements for treat-ment of kidney disease[5]. Nevertheless, novel advances on LN treatment, with the approval of heliumab and vocosporin for‘all patients with active LN’, as well as more recently, the
successful phase 3 trial of obinutuzumab, have provided physi-cians and patients with an expanded armamentarium of agents,necessitating an update of the specific recommendations for kid-ney involvement in SLE.
METHODS
We followed the EULAR standard operating procedures(SOPs)[6] and the Appraisal of Guidelines Research and Evalua-tion(AGREE II) instrument[7]. Following approval by the EULAR Quality of Care Subcommittee and the EULAR Council,the convenor(DB) assembled a multidisciplinary Task Force of 17 rheumatologists, 8 nephroologists, 1 paediatric rheumatolo-gist,1 allied health professional, and 2 patient representatives;among them, there were also 2 methodologists(GB and CAS),2 fellows responsible for the systematic literature reviews(SLR)(AF and MK), and 2 members representing the EMERging EULAR NETwork(EMEUNET)(A-VM and CSS). Importantly, to accom-plish a wider representation, this Task Force included experts outside Europe, specifically 3 from the Americas(1 from the
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USA[RF],1 from Canada[DDG], and 1 from Argentina[AM]),and 2 from Asia(CCM and YT). All members completed a con-flict of interest form.
Following the assembly of the Task Force, an outline of the proposed methodology, a set of the main research questions,and the respective Population, Intervention, Comparison, and Outcomes(PICOs) were circulated among the panelists for their comments, edits, and possible additions. This process resulted in 6 different domains for the SLR:(1) indications for diagnostic kidney biopsy,(2) immune treatment of LN,(3) nonimmune treatment of LN,(4) targets of treatment,(5) duration of treat-ment, and(6) role of repeat kidney biopsy. More details on spe-cific PICO questions and subquestions are provided in a dedicated manuscript regarding the methodology and results of the SLR[8]. Briefly, separate PICOs and search strings were developed for each domain, resulting in 6 different SLRs. The 2 fellows, supervised by the methodologists, searched MEDLINE and EMBASE for English language studies covering the period between January 2019 and end of March 2024(the 2019 recom-mendations on LN had included papers until December 2018).Additional relevant articles identified through manual searches of reference lists from the retrieved publications were also included. Evidence related to the paediatric age groups was included in this process, supported also by the international pae-diatric SHARE LN recommendations[9]. Risk of bias assessment was performed using the Cochrane Risk of Bias tool[10] and Newcastle-Ottawa scale for randomised controlled trials(RCTs)and observational studies[11], respectively. The final level of evidence(LoE; scale: 1-4) and grading of recommendations(scale: A[highest] to D[lowest]), according to the Oxford Cen-tre for Evidence-Based Medicine definitions[12], considered also the body of evidence that had informed the 2019 EULAR/ERA-EDTA recommendations.
The results of the SLRs were presented in detail to the members of the Task Force during a teleconference in Sep-tember 2024, held virtually to facilitate the attendance of the international Task Force members. During a second face-to-face meeting(October 2024), a summary of the SLR results and an initial draft of the statements/recommenda-tions were presented for discussion. Following open delibera-tions during this meeting, the statements were edited, and their final form was voted on by Task Force members present in the meeting. In view of the imminent publication of the phase 3 RCT of obinutuzumab, the Task Force decided to delay finalising the recommendations until publication of this study. Once this study was published and evaluated, obi-nutuzumab was added in 2 recommendations, and a second round of voting took place in February 2025 regarding only these 2 recommendations. Following finalisation, all Task Force members were asked to also provide their level of agreement with each recommendation.
Importantly, the 2019 recommendations for LN included a total of 41 different statements/recommendations, which belonged to 10 different domains(investigation of patient with suspected LN, pathological assessment of kidney biopsy, indica-tions of immunosuppressive treatment, goals of treatment, ini-tial treatment, subsequent treatment, nonresponding/refractory disease, adjunct treatment, monitoring and prognosis of LN,management of end-stage kidney disease in LN, antiphospholi-pid syndrome nephropathy, pregnancy, and management of pae-diatric LN). The current update aimed to comply with the new EULAR SOPs, which suggest a maximum of 15 bullet-point state-ments. To this end, some recommendations from the previous set were omitted and others were merged, while new
recommendations were formulated. Due to these changes, for practical reasons, all overarching principles and individual rec-ommendations of the current update are presented as new, even for recommendations that remain essentially unchanged.According to the EULAR SOPs, a recommendation was accepted if>75% of those present voted in favour. After the finalisation of the recommendation, each member of the panel was then asked to rate their level of agreement(LoA) for every statement on a 0 to 10 numerical rating scale(NRS, 10 being 100% agree-ment). To align with the most recent update of the EULAR SOPs,panelists were also asked to rate each recommendation on the following:(1) its feasibility for implementation in clinical prac-tice, and(2) its impact on quality of care, both using a 0 to 10 NRS. The Task Force selected 3 recommendations with the best balance between feasibility and impact to develop quality indi-cators for future implementation.
RESULTS
The aforementioned procedure resulted in a final number of 4 overarching principles and 13 recommendations, shown in Table 1.
Overarching principles
The overarching principles refer to general information regarding diagnosis and management and reflect good clinical practice; thus, they are not accompanied by a supporting LoE.They nevertheless set the overall framework for the approach to the patients with SLE with kidney involvement and highlight the importance of multidisciplinary assessment and shared phy-sician-patient decision-making.
A. In patients with SLE, regular monitoring for signs and symp-toms of kidney involvement, input from experts, and timely biopsy are essential to ensure optimal outcomes.
Kidney involvement represents a critical event in the natural history of SLE, with profound prognostic repercussions. There-fore, physicians caring for lupus patients should have increased awareness of the development of signs of kidney dis-ease(glomerular haemuria, proteinuria, decreasing glomer-ular filtration rate[GFR]). Although all lupus patients are at risk for LN, closer monitoring may be warranted in subsets with a particularly heightened risk, such as younger patients(paediatric and adults aged<30 years), males, or those with persistent serologic activity(hypocomplementemia and/or positive anti-DNA antibodies)[13]. A kidney biopsy assessed by an experienced nephropathologist, according to the 2003 International Society of Nephrology/Renal Pathology Society classification and its revisions, remains indispensable for the diagnosis of LN and the guidance of therapy[14,15]. With expanding options and increasing complexity of treatment,input from experts and specialised centres is considered essen-tion and optimise prognosis
B. The management of patients with SLE with kidney involvement should align with the general recommendations for SLE, includ-ing treatment with hydroxychloroquine.
The second overarching principle emphasises that kidney involvement is not a separate disease entity from SLE and should be managed according to general disease recommenda-tions(most recent version published in January 2024)[5].This notion is also highlighted in the title of the present
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Table 1
EULAR recommendations for the management of patients with systemic lupus erythematosus and kidney involvement-2025 update
|Overarching principles|Level of agreement|Level of agreement| |---|---|---| |Overarching principles|Mean(SD)|% with score≥8| |A. In patients with SLE, regular monitoring for signs and symptoms of kidney involvement, input from experts, and timely biopsy are essential to ensure optimal outcomes.||| |B. The management of patients with SLE with kidney involvement should align with the general recommendations for SLE, including treatment with hydroxychloroquine.|9.90(0.41)|100| |C. Kidney involvement in SLE carries the risk of progressive chronic kidney disease and is best managed with shared informed patient- physician decisions by rheumatology-nephrology interdisciplinary care teams, with regular assessment of risk factors for chronic kidney disease progression.|9.86(0.44)|100| |D. Management aims to prevent progression of chronic kidney disease and flares, address comorbidities, and improve health-related quality of life; both immunosuppressive and nonimmune therapy, including kidney protection, are essential. Recommendations|9.86(0.35)|100| |1. Kidney biopsy is recommended in type patient with evidence of kidney involvement, especially in those with persistent proteinuria ≥0.5 g/24 h or urine protein-creatinine ratio[UPCR]≥500 mg/g)(2B/b), glomerular haematuria(2B/c), and/or unexplained decrease in glomerular filtration rate(2B/c).|9.86(0.44)|100| |2. Treatment should aim for optimisation(preservation or improvement) of kidney function within 3 months, accompanied by a reduction in proteinuria of at least 25% by 3 months(2B/c), 50% by 6 months(2a/B), and a UPCR target<700 mg/g by 12 months (1B/b), and as low as possible afterwards.|9.83(0.47)|100| |3. For patients with active lupus nephritis, IV pulse methylprednisolone is recommended(2b/C), followed by oral glucocorticoids gradually tapered to≤5 mg/d prednisone-equivalent by 4-6 mo(2B/C), and slowly withdrawn in patients with sustained complete renal response.|9.59(0.68)|100| |4. For patients with active lupus nephritis, especially those with poor prognostic factors, we recommend combination therapy of(a) myphenocolate or low-dose intravenous cyclophosphamide with lemmalum(1b/A),(b) myphenolate with a calcurinine inhibitor (vocloporsin or cartolimus)(1b/A), or (c) mycephonate obutinuzumab(1b/A). Alternative regimens include single-agent therapy therapy with either myphenolate(1a/A) or low-dose intravenous cyclophosphamide(1a/A). 5. In patients with rapidly progressive glomerulosephitis, a short course(6-17 monthly pulses) of high-dose intravenous cyclophosphoma- mide can also be considered(1a/A). 6. Following renal response, treatment should continue for at least 3 years(2b/B); patients initially treated with myophenolate alone(1a/A) or in combination with(1) lemmalibum(1b/A),(2) a calcurinin inhibitor(1b/A), or (3) obutinuzumab" should remain on these drugs; mycophenolate(1a/A) or azothioprine(1a/A) should replace cyclophosphamide for those initially treated with cyclo-phosphamide, alone or in combination with lemmabilum.|9.95(0.78)|96.5| |7. In patients with sustained complete renal response, gradual withdrawal of immunosuppressive and/or biologic therapy should be considered after 3 years of therapy following response, taking into consideration the risk for flare(2a/B).|9.31(1.14)|96.5| |7. In patients with sustained complete renal response, gradual withdrawal of immunosuppressive and/or biologic therapy should be considered after 3 years of therapy following response, taking into consideration the risk for flare(2a/B).|9.31(0.97)|93.1| |8. For patients with persistently active or relapsing disease, switching among the aforementioned immunosuppressive and/or biologic therapy should be 3eR biologic drugs(2b/B) and referral to experts is recommended.|9.72(0.59)|100| |9. Repeat kidney biopsy should be considered, especially in cases of clinical uncertainty, to evaluate(1) response to treatment(2)|9.76(0.58)|100| |worsening of kidney-specific laboratory tests, or(3) contemplated withdrawal of immunosuppressive treatment(2b/B).|9.69(0.71)|96.5| |10. Nonimmune treatment with renin-angiotensin-aldosterone blockade(for patients with persistent proteinuria or arterial hyperten-sion)(5/D), sodium glucose transporter 2 inhibitors(for stable patients with persistent proteinuria or estimated glomerular filtration rate<60 ml/min/m2, or other risk factors for progressive chronic kidney disease)(5/D), statins(based on cardiovascular risk levels) (5/D), and/or bone protective agents(5/D) is recommended.|9.69(0.71)|96.5| |11. In patients with features of thrombotic microangiophathy(antiphospholipid syndrome nephropathy, thrombotic thrombolytic-purpure-like, or complement-mediated bemutic erythemic urechnyl syndrome), glucocorticoids(IV pulse methylprednisolone)(4/C), comple- ment inhibitors(4/C), B-cell depleting agents(4/C), caplacizumab(4/C), plasma exchange(4/C), and/or anticoagulation(2b/C) should be considered.|9.52(0.83)|96.5| |12. In patients with inactive nephritis and adequately controlled extrarenal manifestations, pregnancy may be planned after pre-conception counselling, initiation of pregnancy-compatible medications, and regular multidisciplinary assessments(1b/A).|9.86(0.35)|100| |13. All methods of kidney replacement therapy can be used in patients with SLE; in those with clinically inactive extrareal disease for at least 6 months, transplantation(including living donor and pre-emptive transplantation) should be considered(2b/C).|9.86(0.52)|100| |a Dobutinuzumab was used for a maximum of 1 year(52 weeks) in the REGENCY trial; longer courses await further evaluation. Levels of evidence according to the Oxford Evidence-based Medicine grading levels(https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evi dence-2.1.pdf). NA, not applicable.|||
aObutinuzumab was used for a maximum of 1 year(52 weeks) in the REGENCY trial; longer courses await further evaluation.Levels of evidence according to the Oxford Evidence-based Medicine grading levels(https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evi-dence-2.1.pdf).
NA, not applicable.
update, wherein‘lupus nephritis’ has been substituted by‘kidney involvement’, to denote that SLE is a systemic disease with various manifestations that may manifest over time, even in cases where nephritis can initially present as an organ-domi-nant disease. General management includes non-pharmacologic measures, including sun protection and smoking cessation, as well as the use of hydroxychloroquine(HCQ)[16]. In addition to its multiple benefits in SLE in general, HQC has been associ-ated with better outcomes specifically in LN[17].
C. Kidney involvement in SLE carries the risk for progressive CKD and is best managed with shared informed patient-physician decisions by rheumatology-nephrology interdisciplinary care teams, with regular assessment of risk factors for CKD progression.
The third principle emphasises the concept of CKD in the con-text of LN. CKD is defined as abnormalities of kidney structure or function present for at least 3 months with implications for health and is classified based on cause, GFR(G1-G5), and albu-minuria(A1-A3) categories[18]. CKD is associated with multi-ple adverse outcomes, including cardiovascular morbidity,hospitalisations, and death. Kidney involvement in SLE accel-erates the physiologic nephron loss that occurs with age,decreases the functional kidney reserve, and thus increases the risk for CKD development and progression[19]. This risk cor-relates strongly with a decreased GFR and an increased albu-min-to-creatinine ratio(ACR), especially at levels<60 ml/min/m2 and>30 mg/g, respectively[18,20]. Given the chronic nature of LN and that it often manifests in early adult-hood, measures should be taken to delay the progression of
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CKD. This is especially pertinent in childhood-onset disease, in view of the increased prevalence of kidney involvement and its associated severity in this age group[21].
As both rheumatologists and nephroologists are involved in the care of these patients, an interdisciplinary care team with input from both disciplines is important to ensure optimal out-comes. Age-, ACR-, and GFR-based charts for the estimated risk for CKD are available and should be part of the routine evaluation of patients with SLE with kidney involvement.Treatment decisions should be individualised, considering also patient preferences and their education, as emphasised by the patient research partners in the Task Force.
D. Management aims to prevent progression of CKD and flares,address comorbidities, and improve health-related quality of life; both immunosuppressive therapy and nonimmune therapy,including kidney protection, are essential.
The final overarching principle refers to the long-term goals of management. Prevention of CKD progression is crucial to avoid the long-term sequelae of kidney failure, including car-diovascular disease and infections[17]. To this end, preven-tion of LN flares is of utmost importance because with each flare, damage accumulates, and GFR decline may accelerate[22]. To achieve prevention of CKD progression, both immu-nosuppressive and nonimmune(kidney protective) treatments are needed. Immunosuppression aims to alleviate kidney inflammation and prevent irreversible damage, particularly in the early stages of LN. Long-term preservation of kidney func-tion relies on kidney protective drugs and lifestyle measures that aim to maintain kidney function over time.
Individual recommendations
1. Kidney biopsy is recommended in every patient with evidence of kidney involvement, especially in those with persistent pro-teinuria(≥0.5 g/24 h or urine protein-creatinine ratio≥500 mg/g)(2b/B), glomerular haematuria(2b/C), and/or unex-plained decrease in GFR(2b/C).
This recommendation has remained unchanged from the 2019 update. Patients with SLE and any sign of kidney involvement(glomerular haematuria and/or cellular casts,proteinuria>0.5 g/d[or spot urine protein-to-creatinine ratio[UPCR]>500 mg/g], unexplained decrease in GFR)should be evaluated for a kidney biopsy. The 0.5 g/d pro-teinuria threshold was extensively debated among panelists,considering studies reporting significant rates of prolifer-ative LN in patients with lower proteinuria[23,24], and increasing proteinuria trajectories in some patients who are initially below this threshold[25]. Nevertheless, the Task Force concluded that the decision to perform a kidney biopsy should consider all clinical factors(including extrare-nal disease activity) and laboratory data(such as lupus serology) in each patient[26]; moreover, decision-making may differ in the case of the first diagnosis of LN versus a disease flare. Based on these deliberations, it was decided that the 0.5 g/d threshold should be kept as an indicative threshold to avoid potentially unnecessary biopsies, while not preventing biopsies at lower levels of proteinuria, if indicated. Histologic assessment of the kidney specimen should include elements of active and chronic disease(with computation of the National Institutes of Health[NIH] activity and chronicity indices), tubulointerstitial lesions with prognostic significance(interstitial
inflammation or interstitial fibrosis and tubular atrophy)[27,28], as well as the presence of thrombotic microangi-opathy(TMA, see also recommendation#11).
2. Treatment should aim for optimisation(preservation or improvement) of kidney function within 3 months, accompa-nied by a reduction in proteinuria of at least 25% by 3 months(2b/C), 50% by 6 months(2a/B), and a UPCR target<700 mg/g by 12 months(1b/B), and as low as possible afterwards.
This recommendation has no substantial changes from the 2019 update. No important new data have been added to the post hoc analyses of the MAINTAIN and Euro-Lupus Nephritis Trials, which established that proteinuria at 12 months represents the best predictor for long-term kidney outcome after 10 years[29-31]. Importantly, these targets have been validated in a single observational study[32].Accordingly, the goals of 25% reduction by 3 months, 50%by 6 months), and an absolute UPCR value of<700 mg/g at 12 months remained unchanged; a change from the range of 500 to 700 mg(referred in the 2019 rec-ommendations) was decided for the sake of simplification to provide a fixed threshold for the definition of response at 12 months rather than a range of UPr values, and because this threshold(ie, 700 mg) at 12 months has been associated with good long-term outcome. Complete renal response should be defined as UPCR<500 mg/g at any time point.These values represent suggestive thresholds, since there are patients who start with low-level proteinuria<1 g/d,and others who have severe nephrotic range proteinuria at baseline and may need more time to reach these targets.Together with proteinuria, stabilisation(if not improve-ment) of GFR to≥80% of baseline value is desirable within the first 3 months to ensure that the patient is not deteriorat-ing and in need of reevaluation of the treatment regimen.Notwithstanding its value in detecting kidney involvement,assessing urinary sediment for persistent glomerular haema-turia after treatment initiation has limited independent prognostic value for long-term kidney function[31].
3. For patients with active LN, IV pulse methylprednisolone is rec-ommended(2b/C), followed by oral glucocorticoids gradually tapered to≤5 mg/d prednisone-equivalent by 4 to 6 months(2b/C), and slowly withdrawn in patients with sustained com-plete renal response.
Despite their side effects, glucocorticoids(GCs) remain an integral part of the armamentarium, especially in the early phase of treatment. Nevertheless, the optimal GC regimen and intensity remain unknown, as high-quality randomised studies comparing different regimens are lacking, and their efficacy and speed of action must be balanced against their well-established side effects. A recent meta-analysis of the control arms of RCTs found that a higher initial prednisone dose was associated with higher response rates, but also higher rates of serious infections and death at 6 months[33]. Whether the prednisone dose should be based on patient body weight(mg/kg) or not is also uncertain. A ret-rospective study of 206 patients with LN, using propensity score matching, found higher 1-year complete response rates in those starting with≥40 mg/d compared with≤30 mg/d, without an increased risk of GC-related damage in the higher-dose group[34]. Prednisone dosing based on weight remains the norm in paediatric practice.
The 2019 recommendations specified dose ranges for IV methylprednisolone pulses(total 500-2500 mg, based on disease severity), initial oral prednisone(0.3-0.5 mg/kg/d
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for proliferative LN, 20 mg/d for class V), and tapering tar-gets(≤7.5 mg/d by 3-6 months for proliferal LN,≤5 mg/d by 3 months for class V)[4]. The present update recognises the need for individualisation of GC dosing, tak-ing into consideration LN histology and other parameters(eg, extraral disease activity, risk for GC-associated toxic-ity) and, thus, has omitted specific doses from the statement.In general, pulse IV MP is recommended in the same range of 500 to 2500 mg cumulative dose, administered over 1 to 3 days. Regarding starting oral dose, a dose range of 0.3 to 0.7 mg/kg/d prednisone-equivalent for up to 4 weeks is typ-ically recommended in class III or IV LN. The increase in the upper limit compared with the 2019 recommendations from 0.5 to 0.7 mg/kg/d, in the absence of new data, was decided following discussions among Task Force members, to allow more flexibility to treating physicians for selected cases of severe LN. In the AURORA trial of vocosporin, lower GC doses were used, starting from 25 mg/d, which represents the lowest recommended initial dose. For class V LN with subnephrotic range baseline proteinuria, less intense regi-mens of GC can be used. In patients who improve, oral GC should be gradually tapered to≤5 mg/d by 4 to 6 months and ultimately withdrawn are 12 to 24 months. Importantly,GC reduction and withdrawal are now more feasible with combination therapies, including biologics. Specifically for paediatric patients, the recommended starting dose is 0.6 to 1.0 mg/kg/d. Weaning regimens for this age group may vary, but the overall aim to minimise the overall GC burden and duration of use remains paramount, in view also of lon-ger-term impacts on childhood growth and development, as well as patient choice[35].
4. For patients with active LN, especially those with poor prognos-tic factors, we recommend combination therapy of(a) myco-phenolate or low-dose intravenous cyclophosphamide with belumtabum(1b/A), or(b) mycophenolate with a calcineurin inhibitor(vocsporin or tacrolimus) (1b/A), or(c) mycophe-nolate with obinutuzumab(1b/A). Alternative regimens include single-agent immune therapy with either mycophe-nolate(1a/A) or low-dose intravenous cyclophosphamide(1a/A).
This recommendation marks the most important change of the present update. Since the previous update in 2019, beli-mumab and vocosporin have been approved for the treat-ment of LN, following successful phase 3 RCTs[36,37]. The REGENCY phase 3 RCT of obinutuzumab, a humanised anti-CD20 monoclonal antibody, in combination with mycophe-nolate mofetil(MMF), also met its primary endpoint of com-plete renal response(UPCR<0.5, eGFR>85% of baseline,and no rescue therapy) at 76 weeks[38]. Details on the effi-cacy and safety of these RCTs are provided in the accompa-nying SLR manuscript[8].
After extensive deliberations, the Task Force reached a uniform consensus that, for most patients, initial treatment should include combination therapy-either belimumab with mycophenolic acid analogs (MPAA) or cyclophospha-mide (CYC), or a calcineurin inhibitor (CNI) (tacrolimus or vocosporin) with MPAA, especially in those with poor prog-nostic factors (Table 2). Based on the successful RCT of obi-nutuzumab, obinutuzumab plus MPAA was considered an additional option. While patients with pure class V LN were not included in the REGENCY trial, the Task Force felt it could still be a viable option given its efficacy in mixed pro-iferative and membranous nephritis. Additionally, case
Table 2
Prognostic factors for(1) suboptimal response and development of chronic kidney disease and(2) kidney flares
|Suboptimal response/progression to CKD|Flares| |---|---| |Reduced GFR at baseline (<60 ml/min/m2)|Nonadherence to treatment| |Previous flare|Shorter duration of treatment (<3 years)| |Nephrotic range proteinuria at baseline|Incomplete response following initial therapy| |Hypertension at baseline|Ongoing extrarenal and serologic activity| |Male sex|No use of HCQ| |Increased chronicity index(>3, in the presence of activity)|Young age(<30 years)/male sex| |Histologic evidence of crescents|Residual histologic activity(NIH AI ≥2) at repeat biopsy| |Severe tubulointerstitial inflammation||
GFR, glomerular filtration rate; HCQ, hydroxychloroquine; NIH AI, National Institutes of Health Activity Index.
reports have suggested the efficacy of obinutuzumab in pri-mary membranous nephropathy, and an RCT is currently underway[39]. MPAA or low-dose CYC remain as final options in specific circumstances, explained below.
Important details and arguments that led to the current phrasing can be summarised as follows:(1) kidney involve-ment in SLE by definition constitutes a severe disease presen-tation associated with significant risk for CKD and its progression. Rates of complete response in RCTs remain low(between 20% and 30% at 6 months) indicating a major unmet need, and all 3 drugs(belimumab, voclosporin, and obinutuzumab), in combination with standard of care, have demonstrated superiority over standard of care alone in large phase 3 RCTs;(2) in the recommendation, no distinc-tion is made between proliferative(class III and IV) and membranous(class V) LN classes, which marks a departure from previous recommendations[40,41]. As stated above,patients with pure class V LN were excluded from the phase III RCT of obinutuzumab. Moreover, even in RCTs that included class V LN, these patients are consistently under-represented(~15% of the study population), and conse-quently, these studies were not designed or powered to detect treatment effects specifically in class V;(3) in addi-tion to the different LN classes, the Task Force extensively debated the need to define additional patient subgroups for whom specific combination regimens may be preferred,based on post hoc analyses of the aforementioned RCTs. For example, belimumab was not found to be superior to stan-dard of care in patients with baseline proteinuria>3 g/d[40]; in contrast, both voclosporin and obinutuzumab showed better efficacy in patients with high baseline pro-teinuria[38,42]. In BLISS-LN, only patients who received the combination of belimumab with MMF had better response rates over standard of care; however, only 25% of the study population received belimumab and CYC[36].The Task Force decided to interpret the results of these post hoc subgroup analyses with caution, given that the individ-ual studies were not designed to address efficacy in specific patient subgroups. Accordingly, a deliberate decision was taken to leave the treating physician with a variety of options, until more data become available, including from the real-life use of these drugs;(4) finally, the Task Force
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recognises that there might be circumstances in which sin-gle-agent therapy with either MPAA or low-dose CYC is a reasonable option[43,44]. Such a decision may depend on disease characteristics(eg, a patient with an initial LN flare,low-grade proteinuria with preserved GFR, and mild histo-logic activity), ease of access to new drugs, as well as patient preferences. In this regard, response rates in observational studies tend to be higher than those reported in RCTs(espe-cially in studies from Europe with a higher percentage of white patients)[45-47]. This notwithstanding, the 2025 EULAR update now recommends combination therapy for the majority of patients in healthcare settings with access to all therapeutic options.
Regarding the choice of combination therapy, certain safety considerations should be taken into account. In REGENCY, the obinutuzumab/MMF arm experienced a higher rate of infections than the placebo/MMF arm, mainly due to coronavirus disease 2019(COVID-19)-related neu-monia(5.1% vs 0%, respectively)[38]. Of note, such a sig-nal was not evident in the smaller phase 2 NOBILITY trial of the drug(carried out prior to the COVID-19 era)[48]. In this regard, the B-cell depleting agent rituximab has been associated with a higher risk of infections in patients on prednisolone>10 mg/d, those with serum IgG<6 g/L, or those with multimorbidity[49], as well as with an increased risk for COVID-19.[50] This underlines the need for effec-tive preventive measures, including vaccinations(see rec-ommendation#10). On the other hand, although the risk for nephrotoxicity seems to be lower with vocoplorin than other CNIs, this class of drugs should be avoided(or used with caution) in patients with compromised kidney function(estimated GFR<30-45 ml/min/m2) or substantial fibrosis in the kidney biopsy. Belimumab is not accompanied by sig-nificant safety issues.
Some specifications regarding paediatric disease should also be noted. To date, treatment of childhood-onset LN has generally followed the same principles of adult LN[9].Regarding the newer drugs, belimumab(intravenous) has been approved for paediatric LN since 2022, despite the absence of prospective RCTs(the drug has only been tested in the phase 2 PLUTO trial in extrarenal SLE, with a nonstat-istically significant favourable trend)[51]. By contrast, tri-als of vocosorpin and obutizumab in children with LN are ongoing. Rituximab has been used in observational stud-ies with good efficacy results[52].
5. In patients with rapidly progressive glomerulonephritis, a short course(6-7 monthly pulses) of high-dose intravenous cyclo-phosphamide can also be considered(1a/A).
Recommendation#5 refers to the specific subset of patients who present with rapidly progressive glomerulonephritis,ie, a rapid decline in kidney function accompanied by histo-logic evidence of extensive crescent formation(typically affecting>50% of the glomeruli). Apart from a post hoc analysis of the Aspreva Lupus Management Study in 32 patients with impaired kidney function at baseline, which found similar rates of response in terms of proteinuria and serum creatinine between MMF and high-dose intravenous CYC[43], no high-quality data are available for this sub-group of patients who are underrepresented in clinical trials and carry a poor prognosis. BLISS-LN, REGENCY, and AURORA RCTs excluded patients with low GFR at baseline(<30 in the former two and 45 ml/min/m2 in AURORA,respectively); therefore, recommendations for these patients
are not supported by high-level evidence. Although such patients can still be treated with the regimens mentioned in recommendation#4, a short course of high-dose intrave-nous CYC(modified traditional NIH regimen: 0.5-0.75g/m2 monthly for 6 months, total 6-7 pulses) is an additional option, since it remains the therapeutic regimen most stud-ied in severe LN[53,54]. Combination with monthly pulse methylprednisolone has been shown to improve long-term renal outcome without adding toxicity[54]; therefore, the addition of monthly intravenous pulses of methylpredniso-lone(typically 1 pulse prior to CYC administration) is left to the physician's discretion[54,55]. Administration of monthly gonadotropin-releasing hormone analogs is recom-mended in premenopausal women who receive high-dose intravenous CYC to maximise the possibility of ovarian preservation.
6. Following renal response, treatment should continue for at least 3 years(2b/B); patients initially treated with mycophenolate alone(1a/A) or in combination with(i) belimumab(1b/A),(ii) a calcinurein inhibitor(1b/A), or(iii) obinutuzumab(1b/A) should remain on these drugs; azathioprime(1a/A) or mycophenolate(1a/A) should replace cyclophosphamide for those initially treated with cyclophosphamide, alone or in com-bination with belimumab.
This recommendation refers to what was formerly known as‘maintenance’ or‘subsequent’ therapy; clearly, the terms‘induction’ and‘maintenance’ are no longer suitable in cases where a combination regimen has been chosen from the start. The following principles refer to patients who have responded to initial therapy, as per the targets of treat-ment(recommendation#2). First, the total duration of ther-apy (also addressed in the next recommendation) should be individualised, but generally not be<3 years following response, especially for proliferative classes[56,57]. Sec-ond, long-term treatment should depend on the initially administered regimen. In this regard, the BLISS-LN RCT had a 2-year duration and a long-term extension phase, without major safety signals[36,58]. Advantages of the use of beli-mumab for long-term treatment of LN are its favourable safety profile, established also after over 10 years of real-life use in extraral SLE[59], and the reduction of renal flares shown in BLISS-LN[40]. Regarding combination treatment with MMF/CNI, there is a concern with potential nephrotox-icity associated with long-term CNI use. Importantly, the long-term AURORA-2 study extended the combination of MMF with vocosorpin to 3 years and reported stable GFR levels throughout this period(although the dose of voclo-sporin for a proportion of the patients was reduced over time, which may have influenced its impact on GFR)[60].Regarding combination with tacrolimus, data beyond 2 years are lacking[61]. Lastly, given its higher nephrotoxic poten-tial compared to newer CNIs, cyclosporine is not preferred for long-term treatment. For obinutuzumab, the REGENCY RCT assessed the drug for 12 months(3 cycles every 6 months); thus, if obinutuzumab is to be used, it is currently recommended to follow this regimen, as longer treatment courses will require formal evaluation[38]. Finally, if CYC is used in the initial treatment regimen(either as monother-apy or in combination with belimumab), it should be replaced by MPAA or azathioprine(AZA), preferably the for-mer, except if pregnancy is contemplated. As stated in rec-ommendation#3, in patients who have responded, GC should be tapered to complete discontinuation, if possible,
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by 12 months. For paediatric patients, there is no evidence to suggest that long-term immune treatment of LN should differ from the treatment of adults.
provides treating physicians with a variety of options. Any of the alternative regimens outlined in recommendation#4 can be tried. In cases of monotherapy with MPAA or CYC used as initial therapy, combination therapy should now be strongly considered. In 2019, a recommendation for rituximab was also made in cases of nonresponding disease, based on obser-vational evidence[68]. With the recent success of obinutuzu-mab, it is reasonable that the latter is also an option. B-cell depletion with rituximab can be incomplete and less predict-able in some cases, which affects response to the drug[69].
7. In patients with sustained complete renal response, gradual withdrawal of immunosuppressive and/or biologic therapy should be considered after 3 years of therapy following response, taking into consideration the risk for flare(2a/B).
This recommendation relates to the duration of treatment and, accordingly, optimal timing of immunosuppressive therapy withdrawal(excluding GC, covered in recommen-dation#3). Balancing the need to minimise long-term immunosuppression with the risk of flares after treatment tapering or withdrawal is crucial, as flares may harm the functional reserve of the kidney. In this regard, modifiable risk factors for flare, including nonadherence to treatment,shorter duration of treatment, ongoing externalar and sero-logic activity, no use of HCQ, as well as residual histologic activity despite seemingly clinical inactivity, should be con-sidered(Table 2)[62]. The investigator-initiated WIN-LUPUS RCT compared the continuation versus withdrawal of immunosuppression in patients with LN who had received 2 to 3 years of therapy and were in stable disease(either complete renal remission with proteinuria≤0.2 g/d,or partial with proteinuria≤0.5 g/d, or stable and consid-ered to related or chronic damage, together with inactive urinary sediment and eGFR>90 mL/min/1.73 m2 or≥90%of baseline), for at least 1 year[57]. The study found higher rates of renal(and extrarenal) relapses in the withdrawal group(27.3% vs 12.5%). Notwithstanding this result, recent observational studies have reported satisfactory rates of flare-free immunosuppressive therapy withdrawal. Impor-tantly, longer duration of treatment and remission prior to discontinuation, as well as continued use of HCQ, seem to be consistently associated with a lower risk for flare follow-ing withdrawal of immunosuppression[63,64]. The optimal duration of‘sustained’ complete renal response remains unclear. A different approach may be followed in case of a new-onset vs flaring patients with LN, but sustained com-plete renal response should be considered as no shorter than 12 months in all circumstances[65]. As discussed below(recommendation#9), the decision to withdraw immuno-suppressive treatment can be informed by the findings of repeat kidney biopsy in selected patients, given that residual histologic activity may predict a future relapse[66]; however, this may not be feasible in all settings. In view of this, many experts would treat patients with LN for at least 5 years before considering withdrawal of immunosuppression.
Ultimately, the choice of alternative regimen needs to be individualised and will depend on specific disease charac-teristics(eg, prominent proteinuria, wherein a CNI may be preferable). Given the complexity of the disease and avail-able treatments, referral to or consultation with expert centres is strongly encouraged in nonresponding cases.Emerging evidence for the efficacy of CAR T-cells in cases of multifreactory SLE merits further exploration of this modal-ity for cases of refractory kidney involvement[70].
9. Repeat kidney biopsy should be considered, especially in cases of clinical uncertainty, to evaluate(i) response to treatment,(ii) worsening of kidney-specific laboratory tests, or(iii) con-templated withdrawal of immunosuppressive treatment(2b/B).
This recommendation also does not bear significant changes from the 2019 recommendations. Despite being an invasive procedure, a repeat kidney biopsy provides information that cannot be inferred from clinical and laboratory parameters.Recent observational studies suggest that both activity and chronicity elements in repeat kidney biopsies may be more predictive of long-term GFR decrease or kidney failure, com-pared to baseline biopsies[71-73]. Thus, a second kidney biopsy should be considered if there is clinical uncertainty,including suboptimal response to treatment(to differentiate between ongoing activity and irreversible damage) and/or any worsening of kidney laboratory tests, as in the case of flare(to exclude nonuplus-related causes). A randomised trial, which tests the added value of repeat biopsy at 12 months in patients with LN, is currently underway[74]. An additional scenario, where a second kidney biopsy should be contemplated, is in patients in complete renal response after an adequate duration of immunosuppressive therapy(as defined above). As there is frequent discordance between clinical and histological remission[75], a repeat kidney biopsy may aid in the decision to withdraw immuno-suppressive therapy. In this regard, an observational study in 32 patients showed that ongoing histological activity pre-dicted a subsequent kidney flare after discontinuation of immunosuppression[66], while a retrospective study in patients with repeat biopsy-based management of immuno-suppression reported lower rates of flares, when compared to historical controls[76]. Ultimately, the decision should be individualised and take patient preferences and local expertise into account.
8. For patients with persistently active or relapsing disease,switching among different immunosuppressive(2b/B) and/or biologic drugs(2b/B) and referral to experts is recommended.
This recommendation refers to a disease not responding to initial immunosuppressive therapy and has resulted from merging 2 statements from the 2019 update. Prior to label-ling disease as‘persistently active’ or‘refractory’, it is essential to first evaluate all possible causes of nonresponse.In this regard, assessment of adherence to treatment, includ-ing monitoring drug blood levels where available(eg, for MPAA or CNI), is important[67]. If adherence has been con-firmed, a repeat biopsy may be considered to establish histo-logic activity(see also next recommendation).
10. Nonimmune treatment with renin-angiotensin-aldosterone system blockade(for patients with persistent proteinuria or arterial hypertension(5/D), sodium glucose transporter 2 inhibitors(for stable patients with persistent proteinuria or eGFR<60 ml/min/1.73m2, or other risk factors for progres-sive CKD)(5/D), statins(based on cardiovascular risk levels)(5/D), and/or bone protective agents(5/D) is recommended.This recommendation refers to the second pillar of LN treat-ment, namely nonimmune treatment. It has resulted from
If lack of response is attributed to persistently active disease,the expanded range of available therapies in recent years
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merging 6 different statements from the respective sections in the 2019 recommendations. Major changes include the following:(1) renaming this treatment to‘nonimmune’,rather than‘adjunct’. As outlined also in the overarching principles, this change marks the realisation that nonim-mune, kidney protective treatment is equally important as immune therapies to the long-term preservation of kidney function;(2) the inclusion of sodium glucose transporter 2 inhibitors(SGLT2is) in the therapeutic plan of LN. This class of drugs reduces kidney workload and has been shown to delay the progression of GFR decline in various forms of kid-ney disease[77,78]; of note, these studies also included patients with autoimmune disease-related CKD. Thus,although prospective data are currently lacking in SLE, the Task Force deemed these drugs to be offered to stable patients with persistent proteinuria or eGFR 20 to 60 ml/min/1.73m2(contraindicated in eGFR<20 ml/min) or other risk factors for progressive CKD. It remains unclear whether SGLT2i should be initiated at the outset or after several months of immunosuppressive therapy. However,the Task Force agreed that initiation should be delayed for at least 6 to 12 months until the disease stabilises with immunosuppression. Also, their use in paediatric patients is unclear, because they are not yet indicated in this age subgroup.
Furthermore,renin-angiotensin-aldosterone system(RAAS) blockade is recommended to control blood pressure levels(target<130/80 mm Hg) and also due to its antipro-teinuric effects[79]. Antihypertensives with a different mechanism of action may be used if RAAS blockade is not tolerated, contraindicated(eg, hyperkalaemia, worsening azotaemia), or insufficient. Lifestyle kidney protective meas-ures, including maintenance of a normal body weight,avoidance of smoking and nephrotoxic drugs(eg, nonsteroi-dal antiinflammatory drugs), and salt restriction, are of utmost importance[19]. Anticoagulation therapy should be temporarily administered in patients with nephrotic syndrome and severe hypoalbuminemia(albumin levels<2-2.5g/dL). For infection prevention due to the com-bined and prolonged immunosuppression, patients should be initially screened for possible latent or resolved infections(HBV, HCV, and tuberculosis) and receive prophylaxis when indicated. Patients should also be vaccinated with nonlive vaccines, including against influenza, Streptococcus pneumoniae, SARS-CoV-2, and herpes zoster[80]. Regarding protection from cardiovascular acular disease, patients should be assessed for their 10-year cardiovascular risk according to one of the available validated scores[81], based on lipid levels and presence of other cardiovascular risk factors, and therapy with sta-tins should be considered accordingly[82]. Bone protec-tion and prevention of osteoporosis should follow nonpharmacologic(exercise uptake, normal body mass index), as well as pharmacologic measures, according to individual fracture risk. Bisphonosphonates should be used with caution in patients with reduced GFR.
11. In patients with features of thrombotic microangiopathy(anti-phospholipid syndrome nephropathy, thrombotic thrombocyto-penic purpurea-like, or complement mediated hemolytic uremic syndrome), GCs(including pulse IV methylprednisolone)(4/C),complement inhibitors(4/C),B-cell depleting agents(4/C),caplacizumab(4/C), plasma exchange(4/C), and/or anticoagulation(2b/C) should be considered.
In recent years, the concept of TMA in SLE has evolved to encompass syndromes of various underlying aetiologies,ranging from classic thrombotic thrombocytopenic pur-pura(TTP), via complement-mediated hemolytic uremic syndrome(CM-HUS), to antiphospholipid syndrome(APS)nephropathy. These syndromes share the clinical picture of TMA, yet have distinct pathophysiologic mechanisms and may respond to different therapies. To this end, a diagnosis of TMA in the context of LN(histologic evidence of TMA,microangiopathic haemolytic anaemia and thrombocyto-penia, involvement of the central nervous system) should prompt a diagnostic workup towards the underlying patho-physiology, in order to guide targeted treatment. The pres-ence of low ADAMTS13 activity confirms a diagnosis of TTP, wherein plasma exchange is recommended, followed by immunosuppressive treatment for LN. Caplacizumab, a bivalent variable domain-only immunoglobulin fragment against von Willebrand factor approved for the treatment of acquired TTP[83], can be considered in nonresponding TTP patients, although data in patients with SLE are cur-rently limited to a few case reports. The use of complement inhibitors(eculizumab and ravulizumab) should be consid-ered if TTP has been ruled out and activation of the com-plement pathway remains as the suspected underlying aetiology(CM-HUS). Accumulating observational data suggest that complement inhibitors may be particularly effective in the subset of patients with CM-HUS with signif-icant kidney injury[84,85]. Finally, anticoagulation is rec-ommended in the presence of TMA accompanied by positive antiphospholipid antibodies, especially at high titres, which establishes the diagnosis of APS nephropathy[86].
12. In patients with inactive nephritis and whose extrarenal mani-festations are adequately controlled, pregnancy may be planned after preconception counselling, initiation of preg-nancy-compatible medications, and regular multidisciplinary assessments(1b/A).
The 2019 recommendations included a section with 6 state-ments regarding pregnancy in patients with LN, including optimal timing, compatible medications, use of aspirin, and need for multidisciplinary assessment. Since no significant new data have emerged following the previous update, the section has now been merged into a single recommendation,without major contextual changes. EULAR has issued spe-cific recommendations for family planning in SLE, including pregnancy and lactation[87]. A history of kidney involve-ment poses significant risks for mother and foetus; thus, the value of preconception counselling cannot be overemphas-ised. Active LN, especially with impaired kidney function, is a relative contraindication for pregnancy, which should be postponed until the disease is controlled and stable for at least 6 months. Inactive disease would ideally necessitate a kidney biopsy to show the absence of histologic activity, but this is not available in most circumstances. The ideal clinical scenario would be a patient with normal kidney function and blood pressure and a UPCR<500 mg/g, but this may often not be achievable. To this end, pregnancy should be contemplated only in patients with stable LN and following risk stratification based on CKD stage[88].
Pregnancy-compatible medications include GC, AZA, and CNI, which should be continued throughout pregnancy and lactation, along with HQC(currently, there is insufficient evidence regarding the safety of voclosporin during
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pregnancy/lactation)[89]. Blood pressure should be con-trolled without the use of RAAS inhibitors, which are terato-genic in the first trimester. The use of low-dose aspirin is recommended because a history of LN increases the risk of preeclampsia. Immunosuppressive drugs, which are contra-indicated in the first trimester(eg, MPAA, CYC), may be considered in the second or third trimester for life-threatening disease; B-cell depleting agents should be avoided in the third trimester due to possible neonatal hypogammaglobi-nemia and compromised response to vaccinations. Finally,pregnancy in patients with a history of kidney involvement should be monitored by a multidisciplinary team, including an obstetrician with expertise in the disease and high-risk pregnancies.
13. All methods of kidney replacement therapy can be used in patients with SLE; in those with clinically inactive externalar disease for at least 6 months, transplantation(including living donor and preemptive transplantation) should be considered(2b/C).
The final recommendation has also remained essentially unchanged from the 2019 update. Once a patient with LN reaches kidney failure, all methods of kidney replacement therapy can be used. Preemptive transplantation is associ-ated with better 10-year kidney survival rates [90,91]; how-ever, only a small proportion of patients are currently offered this possibility. Transplantation should not be delayed in patients who are in remission or sustained low extrarenal disease activity (eg, sustained lupus low disease activity state) [92]. Regarding haemodialysis and continu-ous peritoneal dialysis, a meta-analysis showed no differ-ence in the risk for disease flares, all-cause infections, and mortality, although a higher risk for all-cause cardiovascular events was evident for haemodialysis (relative risk 1.44)[93]. Recent data from the ERA registry suggest that the prognosis of patients with lupus receiving kidney replace-ment therapies has improved over time, with better 10-year patient survival rates, which are similar to patients who
<EndOfPara>required kidney replacement therapies for other causes of kidney failure(HR 1.11)[94].
The same principles apply in paediatric patients. Yet, a recent US retrospective cohort study suggested that children and adolescents with LN on dialysis may carry a higher risk for adverse outcomes, including hospitalisation, and are less likely to receive kidney transplantation compared to chil-dren with other causes of kidney failure[95].
Construction of quality indicators
We chose the 3 recommendations with the best balance between feasibility and impact on quality of care to construct respective quality indicators(Supplementary Table 1). These were recommendations\#4,6, and 10 and are the ones that focus on immune(\#4,6) and nonimmune(\#10) treatment of kidney involvement in SLE. The proposed quality indicators are shown in Table 3, and their implementation will be tested following publication of the recommendations.
DISCUSSION
Following years of failures of clinical trials, the recent pace of therapeutic advances for patients with SLE and kidney involve-ment has accelerated[96]. Herein, we gathered a multidisciplin-ary and multinational panel of LN experts across 3 continents to ensure the widest possible representation and broadest exper-tise. To emphasise the concept that kidney involvement in SLE is a manifestation of a multisystem disease, even when it domi-nates the clinical picture, the project was entitled‘Recommendations for the management of SLE with kidney involvement',rather than‘LN’.
A major modification of the present update compared to the 2019 EULAR-ERA/EDTA recommendations is the drastic reduc-tion in the total number of individual recommendations, in line with the current EULAR SOPs. The consolidation of the state-ments to 4 overarching principles and 13 individual
Table 3
EULAR recommendations for the management of patients with systemic lupus erythematosus and kidney involvement-2025 update: Quality Indicators
||When to measure|How to measure| |---|---|---| |Q11 Immune therapy|At the initiation of|Clinical audit| |If a patient with SLE has active nephritis, THEN combination therapy should be administered-especially if poor prognostic factors are present- consisting of either(1) mycophenolate or low-dose intravenous cyclophosphamide with heliumab, (2) mycophenolate with a calcineurin inhibitor(vocspiovor or tacclinus, or(3) mycophenolate with obutinuzabum.Alternative regimens include therapy with either mycophenolate or low-dose intravenous cyclophosphamide for selected patients.|treatment|| |Q12 Duration of therapy|Month 6 onwards, following|Clinical audit| |If a patient with nephritis responds to initial treatment, THEN treatment should continue for at least 3 years, based on the initial regimen. Patients initially treated with mycophenolate alone or in combination with(1) belimumab,(2) calcineurin inhibitor, or(3) obutinuzabum should remain on these drugs. Mycophenolate or azathioprime should replace cyclophosphamide for those initially treated with cyclophosphamide, alone or in combination with belimumab.|initiation of treatment|| |Q13 Nonimmune therapy|Month 6 onwards following|Clinical audit| |If a patient with SLE has kidney involvement, THEN nonimmune treatment with RAAS blockade (for patients with persistent proteinuria or arterial hypertension), SGLT2 inhibitors (for stable patients with persistent proteinuria or gEFR<60 ml/min/ m2, or other risk factors for progressive CDK), statins (based on cardiovascular risk levels), and/or bone protective agents should be given, as appropriate.|immunosuppressive treatment||
${}^{a}$ Obinutuzumab was used for a maximum of 1 year(52 weeks) in the REGENCY trial; longer courses await further evaluation.
${}^{b}$ This QI spans the whole period of treatment. The 6-month time point is an indicative starting point, when adherence to this recommendation should be evaluated.
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium glucose transporter 2.
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recommendations attempts to summarise the major directions in a simple, yet not simplistic, way, to facilitate the dissemination and implementation of the recommendations in clinical prac-tice. These major pillars of management are summarised in the Figure. The accompanying text of the recommendations will provide the reader with a more thorough understanding of the supporting data behind each statement. In this regard, no signifi-cant changes have been made regarding indications for a diag-nostic kidney biopsy, goals of treatment, issues of pregnancy,and management of LN-kidney failure, and the respective rec-ommendations have remained essentially unchanged. Little progress has also been made regarding the optimal use of GC in LN, both in terms of starting dose and tapering strategies. For this reason, apart from a universal recommendation for IV meth-ylprednisolone pulses, the recommendations provide a range of starting doses, based on physician discretion, as well as a gen-eral guidance that, in patients who respond, GC should be with-drawn within the first 1 to 2 years.
The current update marks a paradigm shift for the immuno-suppressive treatment of patients with SLE with kidney involve-ment. EULAR now recommends an initial combination regimen of MPAA with belimumab, a CNI, or obinutuzumab(plus GC)for all patients with active LN, especially those with adverse risk factors at baseline. This recommendation comes only 1 year after the publication of the EULAR recommendations for the management of general SLE, wherein it was stated that combina-tion regimens‘should be considered’ for all patients. Therein,single-agent therapy with either MPAA or CYC was still recom-mended. This gradual shift in phrasing was the combination of both evidence-based(superiority of combination treatments
over monotherapy in high-quality phase 3 RCTs) and the opin-ion of experts within the Task Force. Indeed, combination treat-ments are being increasingly used in clinical practice and tend to become standard of care early, at least in healthcare settings with access to these drugs. Nevertheless, single-agent therapy with drugs with an established record in LN is still an option,especially in the absence of poor prognostic factors and in coun-tries with limited access to new therapies.
B-cell depletion has long been considered an attractive ther-apy for kidney involvement in SLE. Despite the failed LUNAR trial[97], rituximab has been extensively used mainly in refrac-tory cases of LN. The recent successful trials of obinutuzumab,which induces a more consistent depletion of B-cells compared to rituximab, have reignited interest in B-cell depletion as first-line treatment in LN. Although there has been extensive experi-ence with obtutuzumab in hematologic malignancies, real-life experience in LN is limited. The potentially increased risk for infections that accompanies B-cell depleting therapies may be mitigated in part by decreased doses of GC in current regimens and the availability of effective vaccines. Rituximab may still be considered if other options have failed and obinutuzumab is unavailable. The potential of deep B-cell depletion in SLE is also supported by the recent successful case series of both CAR T-cells and bispecific T-cellagers, but these treatments await confirmation in larger randomised trials[70,98].
The second important shift in the current recommendations is the upgrading of the importance of kidney protective treat-ment for the long-term management of LN, reflected both in the overarching principles and recommendation#9. For years,immunosuppressive treatment has monopolised interest(and
EULAR Recommendations for SLE with Kidney Involvement(2025)
Diagnosis/Targets
Immune treatment
Non-immune treatment
Severe or Refractory
Kidney biopsy
Early combination therapy
Kidney protection
RPGN
$\begin{array}{l}\text{ Indispensable for diagnosis;}\\ \text{ repeat in case of uncertainty}\\ \text{ regarding response to treatment}\end{array}$
HCQ and glucocorticoids with immunosuppressive and CNI or biologic
- Low salt(less than 5 g/day)
•Consider high-dose IV-CY plus pulse IV-MP
-Control blood pressure(RAAS blockade 1#choice)
Refractory
-Assess patient adherence first
Target- Prevention of
● Glucocorticoids
-Start with pulses
-Chronic kidney disease
-Continue with 0.3-0.7 mg/kg/day prednisone
-Flares
-Taper to 5≤mg/day by 6-6 months and withdraw, when possible
Milestones
Immunosuppressives
-Kidney function: Preservation or improvement by 3 months
-MPA, low-dose IV-CY
-Proteinuria:
CNI
*Reduction by 25% at 3 mo
- Vocosporin or TAC
* Reduction by 50% by 6 mo
● Biologics
Belimumab,Obinutuzumab
Refractory
-Assess patient adherence first
- Combination of IV-CY with B cell depletion
- Addition of a CNI if heavy Proteinuria
Experimental therapies in the context of clinical trials
Thrombotic microangiopathy
- Plasma exchange
-Complement inhibitors
-Anti-Wf9(caplacizumab)
Figure. Overview of the treatment strategy for SLE with kidney involvement and its key targets, milestones, and pillars of therapy. Early kidney biopsy and early initiation of combination treatment, especially for patients with adverse renal factors, are of paramount importance. Patients with adverse prognostic factors are more likely to receive more intense therapy for longer periods of time. Aggressive glucocorticoid tapering to a minimal prednisone equivalent of≤5 mg/d or discontinuation, along with immunosuppressive and biologic therapy for at least 3 years after achieving a com-plete response, is recommended. Background use of antimalarials, immunisations, and kidney protection with control of blood pressure and antiprotei-nuric agents for patients with residual proteinuria after 6 to 12 months are additional measures to ensure optimal long-term outcomes. Doses of drugs:HCQ:5 mg/kg/d(up to 400 mg/d);MPAA,mycophenolate mofetil 1-1.5 g twice daily-mycophenolate sodium 720-1080 mg twice daily; low-dose IV-CY:500 mg on weeks 0,2,4,6,8, and 10;covlocoris:237.7 mg twice daily: TAC 0.05 to 0.1 mg/kg/d initially, titrated to target blood concentra-tion 4-6 ng/ml 12 hours after dose; bilumemin: SC 400 mg weekly for 4 doses, then 2006 once weekly or IV 10 mg/kg every 2 weeks for the first 3 doses and every 4 weeks thereafter,outbinum: 1000 mg on days 1 and 15-readimitration at 6 months. CNI, calcineurin inhibitor; CSA, cyclo-sporine A; HCQ,hydroxychloroquine; HZV,berpesister;IV-CYC,intravenous cyclophosphamide; MPAA,mycophenolate acid analogs; RAAS, renin-angiotensin-andlocerostone system; RPGN, rapidly progressive glomerulonephritis; SGLT2, sodium glucose transporter 2; TAC, tacrolimus; UPCR, urine protein-to-reatinine ratio; WW, von Willebrand factor.
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research) as the single most important pillar of treatment. The recent advent of new drugs with kidney protective properties over a spectrum of diseases associated with CKD(SGLT2i, min-eralocortic receptor antagonists, endothelin receptor antagora-nists) has helped to realise that prevention of CKD occurrence and progression-the ultimate goal of treatment in LN-is best served by the combination of immunosuppression and kidney protection. This two-arm therapy illustrates the crucial impor-tance of multidisciplinary management and monitoring of these patients, expressed also as a wish by the patient representatives in the Task Force. Nephrologists are typically more familiar with the use of kidney protective drugs and advice on respective lifestyle measures, whereas rheumatologists approach lupus patients from the perspective of a systemic disease and focus also on extraren manifestations.
Recommendations provide a framework for the state-of-the-art management of a disease, yet their implementation in real-life clinical practice is often suboptimal for a variety of reasons[9].Following the 2019 EULAR recommendations for the manage-ment of general SLE, we created a list of quality indicators[100];these were validated both internally, as well as independently in a cohort of patients in relation to their quality of life[101].EULAR now specifies in its SOPs that specific measures should be taken following the publication of a set of recommendations, to maximise the possibility of their implementation[102]. To this end, we have constructed 3 key quality indicators-balanced for feasibility and impact-in tabular form based on the current rec-ommendations to serve as a checklist for physicians who treat patients with SLE with kidney involvement. Finally, an agenda with questions for future research is shown in Table 4.
In summary, we have updated the EULAR recommendations for SLE with kidney involvement, in view of significant recent advances, to provide physicians with evidence- and
Table 4
Research agenda in SLE with kidney involvement
Diagnosis
•Atypical presentations: podocypathies and pauci-lumune hippocus nephritis,other forms
● Validated definition of kidney flares
Therapies and disease monitoring
Early disease and therapeutic window of opportunity
● Mechanisms of severe refractory disease
B-cell depleting therapies, including CAR-T cells and bispecific T-cell engagurs
Combination of B-cell depleting with B-or T-cell-modifying therapies
● Improvement of complete renal response rates and deep flare-free remission
•'Add-on' therapies to achieve deep remission
● Imaging for kidney fibrosis
Duration and withdrawal of therapy
● Protocolised repeat biopsics value: early of early vs late repeat biopsy
● Efficacy of different treatments for various forms of SLE-associated TMA with kidney involvement
● Drug level monitoring and improvement of compliance with treatment
Nonimmune mechanisms in the progression of kidney disease, such as hyper-tension, obesity, and dyslipidaemia
● Optimal timing of SGLT2i initiation in SLE with kidney involvement
Pathophysiology and biomarkers
● Biomarkers for liquid biopsy
● Risk stratification of subgroups based on molecular signatures or other biomarkers
•Noninvasive means to classify the types of SLE with kidney involvement and activity status(inr cells, omics, etc)
Renal progenitor cells and their proliferation in SLE with kidney involvement
● Kidney repair in SLE with kidney involvement
Lupus Nephritis Trial Design
● Better definition of clinical trial endpoints
●Optimisation of'standard-of-care'(background) treatments
● Trials on class V up nephusribs
eminence-based guidance. Together with the recently published KDIGO recommendations[103] and the American College of Rheumatology guidelines[104], physicians will now have more evidence to base their therapeutic decisions for this challenging manifestation of lupus.
Competing interests
AF reports lecture or consultancy fees from AstraZeneca,GSK, Boehringer Ingelheim, Genesis Pharma, Pfizer, AbbVie,Eli Lilly. MK reports honoraria and/or consulting fees from GSK, participation in advisory boards from GSK, AstraZeneca,and Amgen. HJA reports lecture or consultancy fees from Astra-Zeneca, GSK, Novartis, Boehringer Ingelheim, Roche, and Otsuka. JA reports no direct conflict of interest, but LUPUS EURO is funded by grants or donations from Pharmaceutical Companies(Amgen/Horizon, AstraZeneca, Biogen, BMS, Gala-pagos, GSK, Viarris, Johnson& Johnson, Merck, Novartis,Otsuka, Roche, and UCB); none of which exceeds 25% of total funds collected, and none having a say on the content of studies or work by LUPUS EURO. MA reports advisory boards and/or lectures for AstraZeneca, GSK, Otsuka, and Roche. RF reports consulting fees from Genentech, GSK, Aurinia, Alexion, AstraZe-neca, BMS, Novartis, Kyverma, and Boehringer Ingelheim. FH reports research grants from GSK and Roche and consulting/advisory fees from Neovacs, GSK, AstraZeneca, Eli Lilly, Idorsia,Otsuka, Biogen, and Galapagos. AK reports consultant fees from GSK, Vifor, Novartis, Otsuka, and Roche and honoraria from Pfizer, AstraZeneca, GSK, Novartis, Vifor, Otsuka, and Boeh-ringer Ingelheim. AM reports advisory and speaker fees from GSK, Pfizer, Kezar, Roche, BMS, Novartis, and Biogen. AVM is funded by the National Institute for Health and Care Research(NIHR) Manchester Biomedical Research Centre(BRC)(NIHR203308)(the views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care) and reports grant support from UCB and Jans-sen. GM reports speaker fees from GSK, Otsuka, and Vifor. IP reports research funding and/or honoraria from Amgen, Astra-Zeneca, Aurinia, BMS, Eli Lilly, Gilead, GSK, Janssen, Novartis,Otsuka, and Roche. YT reports speaking fees and/or honoraria from Chugai, UCB, AbbVie, AstraZeneca, Eli Lilly, Behringer Ingelheim, GSK, Eisai, IQVIA, Daiichi-Sankyo, Otsuka, Taisho,Gilead, and BMS. GB has received honorary fees from GSK, Abb-Vie, AstraZeneca, UCB, Lilly, Otsuka, and Novartis and grants from MSD, AstraZeneca, and GSK. DTB reports unrestricted investigational grants from GSK and honoraria/consulting fees from GSK, AstraZeneca, AbbVie, Aenorasis, and Pfizer. The remaining authors declare no conflicts of interest.
CRediT authorship Contribution statement
Antonis Fanourakis: Writing- original draft, Methodol-ogy,Formal analysis,Data curation.Myrto Kostopoulou: Meth-odology, Data curation. Hans-Joachim Anders: Writing-review& editing. Jeanneanders: Wenriting- review& edit-ing. Martin Aringer: Writing- review& editing. Michael W.Beresford: Writing-review& editing. Andrea Doria: Writing-review& editing. Eleni Frangou: Writing-review& editing.Richard Furie: Writing- review& editing. Dafna D. Glad-man: Writing-review& editing. Frederic Houssiaau: Writing- review& editing. Alexander Krearras: Writing- review&editing. Marios Kouloumas: Writing-review& editing. Anas-tasia-Vasiliiki Madenidou: Writing- review& editing. Ana Malvar: Writing- review& editing. Smaragdi Marinaki:
A. Fanouriakis et al.
Ann Rheum Dis 00(2025) 1-16
Writing- review& editing. Chi Chiu Mok: Writing- review&editing. Gabriella Moroni: Writing- review& editing. Ioannis Parodis: Writing- review& editing. Simona Rednic: Writing- review& editing. Christiana Siero Santos: Writing- review& editing. Carlo Alberto Scire: Methodology. Josef S. Smolen:Writing- review& editing. Farah Tamora: Wirft- review- review& editing. Yoshiya Tanaka: Writing- review& editing. Y.K.Onno Teng: Writing- review& editing. Elisabet Welin: Writ-ing- review& editing. George Bertias: Writing- review&editing. Supervision, Methodology. Dimitrios T. Boumpas:Writing- review& editing. Supervision, Supervision Conceptualization.
Acknowledgements
The Task Force wishes to acknowledge the support of the EULAR Quality of Care Committee. The committee also expresses its sincere appreciation and gratitude to the EULAR Secretariat and especially to Simona Lupatin, executive assis-tant, for the outstanding organisation. We thank Maria Pappa and Katerina Chavatza for providing useful feedback on the manuscript, as well as Spirosates which for preparing the sum-mary figure.
Funding
This project was funded by the European Alliance of Associa-tions for Rheumatology(QCoO22).
Patient consent for publication
Not applicable.
Ethics approval
Not applicable.
Provenance and peer review
Not applicable.
Supplementary materials
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.ard.2025.09.007.
Orcid
Antonis Fanourakis: http://rcid.org/0000-0003-2696-031X
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| Overarching principles | Level of agreement | Level of agreement |
|---|---|---|
| Overarching principles | Mean(SD) | % with score≥8 |
| A. In patients with SLE, regular monitoring for signs and symptoms of kidney involvement, input from experts, and timely biopsy are essential to ensure optimal outcomes. | ||
| B. The management of patients with SLE with kidney involvement should align with the general recommendations for SLE, including treatment with hydroxychloroquine. | 9.90(0.41) | 100 |
| C. Kidney involvement in SLE carries the risk of progressive chronic kidney disease and is best managed with shared informed patient- physician decisions by rheumatology-nephrology interdisciplinary care teams, with regular assessment of risk factors for chronic kidney disease progression. | 9.86(0.44) | 100 |
| D. Management aims to prevent progression of chronic kidney disease and flares, address comorbidities, and improve health-related quality of life; both immunosuppressive and nonimmune therapy, including kidney protection, are essential. Recommendations | 9.86(0.35) | 100 |
| 1. Kidney biopsy is recommended in type patient with evidence of kidney involvement, especially in those with persistent proteinuria ≥0.5 g/24 h or urine protein-creatinine ratio[UPCR]≥500 mg/g)(2B/b), glomerular haematuria(2B/c), and/or unexplained decrease in glomerular filtration rate(2B/c). | 9.86(0.44) | 100 |
| 2. Treatment should aim for optimisation(preservation or improvement) of kidney function within 3 months, accompanied by a reduction in proteinuria of at least 25% by 3 months(2B/c), 50% by 6 months(2a/B), and a UPCR target<700 mg/g by 12 months (1B/b), and as low as possible afterwards. | 9.83(0.47) | 100 |
| 3. For patients with active lupus nephritis, IV pulse methylprednisolone is recommended(2b/C), followed by oral glucocorticoids gradually tapered to≤5 mg/d prednisone-equivalent by 4-6 mo(2B/C), and slowly withdrawn in patients with sustained complete renal response. | 9.59(0.68) | 100 |
| 4. For patients with active lupus nephritis, especially those with poor prognostic factors, we recommend combination therapy of(a) myphenocolate or low-dose intravenous cyclophosphamide with lemmalum(1b/A),(b) myphenolate with a calcurinine inhibitor (vocloporsin or cartolimus)(1b/A), or (c) mycephonate obutinuzumab(1b/A). Alternative regimens include single-agent therapy therapy with either myphenolate(1a/A) or low-dose intravenous cyclophosphamide(1a/A). 5. In patients with rapidly progressive glomerulosephitis, a short course(6-17 monthly pulses) of high-dose intravenous cyclophosphoma- mide can also be considered(1a/A). 6. Following renal response, treatment should continue for at least 3 years(2b/B); patients initially treated with myophenolate alone(1a/A) or in combination with(1) lemmalibum(1b/A),(2) a calcurinin inhibitor(1b/A), or (3) obutinuzumab" should remain on these drugs; mycophenolate(1a/A) or azothioprine(1a/A) should replace cyclophosphamide for those initially treated with cyclo-phosphamide, alone or in combination with lemmabilum. | 9.95(0.78) | 96.5 |
| 7. In patients with sustained complete renal response, gradual withdrawal of immunosuppressive and/or biologic therapy should be considered after 3 years of therapy following response, taking into consideration the risk for flare(2a/B). | 9.31(1.14) | 96.5 |
| 7. In patients with sustained complete renal response, gradual withdrawal of immunosuppressive and/or biologic therapy should be considered after 3 years of therapy following response, taking into consideration the risk for flare(2a/B). | 9.31(0.97) | 93.1 |
| 8. For patients with persistently active or relapsing disease, switching among the aforementioned immunosuppressive and/or biologic therapy should be 3eR biologic drugs(2b/B) and referral to experts is recommended. | 9.72(0.59) | 100 |
| 9. Repeat kidney biopsy should be considered, especially in cases of clinical uncertainty, to evaluate(1) response to treatment(2) | 9.76(0.58) | 100 |
| worsening of kidney-specific laboratory tests, or(3) contemplated withdrawal of immunosuppressive treatment(2b/B). | 9.69(0.71) | 96.5 |
| 10. Nonimmune treatment with renin-angiotensin-aldosterone blockade(for patients with persistent proteinuria or arterial hyperten-sion)(5/D), sodium glucose transporter 2 inhibitors(for stable patients with persistent proteinuria or estimated glomerular filtration rate<60 ml/min/m2, or other risk factors for progressive chronic kidney disease)(5/D), statins(based on cardiovascular risk levels) (5/D), and/or bone protective agents(5/D) is recommended. | 9.69(0.71) | 96.5 |
| 11. In patients with features of thrombotic microangiophathy(antiphospholipid syndrome nephropathy, thrombotic thrombolytic-purpure-like, or complement-mediated bemutic erythemic urechnyl syndrome), glucocorticoids(IV pulse methylprednisolone)(4/C), comple- ment inhibitors(4/C), B-cell depleting agents(4/C), caplacizumab(4/C), plasma exchange(4/C), and/or anticoagulation(2b/C) should be considered. | 9.52(0.83) | 96.5 |
| 12. In patients with inactive nephritis and adequately controlled extrarenal manifestations, pregnancy may be planned after pre-conception counselling, initiation of pregnancy-compatible medications, and regular multidisciplinary assessments(1b/A). | 9.86(0.35) | 100 |
| 13. All methods of kidney replacement therapy can be used in patients with SLE; in those with clinically inactive extrareal disease for at least 6 months, transplantation(including living donor and pre-emptive transplantation) should be considered(2b/C). | 9.86(0.52) | 100 |
| a Dobutinuzumab was used for a maximum of 1 year(52 weeks) in the REGENCY trial; longer courses await further evaluation. Levels of evidence according to the Oxford Evidence-based Medicine grading levels(https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evi dence-2.1.pdf). NA, not applicable. |
| Suboptimal response/progression to CKD | Flares |
|---|---|
| Reduced GFR at baseline (<60 ml/min/m2) | Nonadherence to treatment |
| Previous flare | Shorter duration of treatment (<3 years) |
| Nephrotic range proteinuria at baseline | Incomplete response following initial therapy |
| Hypertension at baseline | Ongoing extrarenal and serologic activity |
| Male sex | No use of HCQ |
| Increased chronicity index(>3, in the presence of activity) | Young age(<30 years)/male sex |
| Histologic evidence of crescents | Residual histologic activity(NIH AI ≥2) at repeat biopsy |
| Severe tubulointerstitial inflammation |
| When to measure | How to measure | |
|---|---|---|
| Q11 Immune therapy | At the initiation of | Clinical audit |
| If a patient with SLE has active nephritis, THEN combination therapy should be administered-especially if poor prognostic factors are present- consisting of either(1) mycophenolate or low-dose intravenous cyclophosphamide with heliumab, (2) mycophenolate with a calcineurin inhibitor(vocspiovor or tacclinus, or(3) mycophenolate with obutinuzabum.Alternative regimens include therapy with either mycophenolate or low-dose intravenous cyclophosphamide for selected patients. | treatment | |
| Q12 Duration of therapy | Month 6 onwards, following | Clinical audit |
| If a patient with nephritis responds to initial treatment, THEN treatment should continue for at least 3 years, based on the initial regimen. Patients initially treated with mycophenolate alone or in combination with(1) belimumab,(2) calcineurin inhibitor, or(3) obutinuzabum should remain on these drugs. Mycophenolate or azathioprime should replace cyclophosphamide for those initially treated with cyclophosphamide, alone or in combination with belimumab. | initiation of treatment | |
| Q13 Nonimmune therapy | Month 6 onwards following | Clinical audit |
| If a patient with SLE has kidney involvement, THEN nonimmune treatment with RAAS blockade (for patients with persistent proteinuria or arterial hypertension), SGLT2 inhibitors (for stable patients with persistent proteinuria or gEFR<60 ml/min/ m2, or other risk factors for progressive CDK), statins (based on cardiovascular risk levels), and/or bone protective agents should be given, as appropriate. | immunosuppressive treatment |
引用 / 出处
2025+EULAR建议：累及肾脏的系统性红斑狼疮的管理（更新版）. 2025.