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Article Contents

Lay summary, introduction, 1. diagnosis, 2. monitoring of lupus nephritis after diagnosis, 3. definitions and treatment objectives, 4. treatment of lupus nephritis: induction and maintenance, 5. special situations, 6. holistic approach to lupus nephritis patients: preventive actions, and control of comorbidities and therapy toxicity, acknowledgements, authors’ contributions, conflict of interest statement, data availability statement.

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Diagnosis and treatment of lupus nephritis: a summary of the Consensus Document of the Spanish Group for the Study of Glomerular Diseases (GLOSEN)

These authors contributed equally to the manuscript.

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• Figures & tables
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Jorge E Rojas-Rivera, Clara García-Carro, Ana I Ávila, Mar Espino, Mario Espinosa, Gema Fernández-Juárez, Xavier Fulladosa, Marian Goicoechea, Manuel Macía, Enrique Morales, Luis F Quintana, Manuel Praga, Diagnosis and treatment of lupus nephritis: a summary of the Consensus Document of the Spanish Group for the Study of Glomerular Diseases (GLOSEN), Clinical Kidney Journal , Volume 16, Issue 9, September 2023, Pages 1384–1402, https://doi.org/10.1093/ckj/sfad055

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Lupus nephritis (LN) is the most frequent serious manifestation of patients with systemic lupus erythematosus (SLE). Up to 60% of SLE patients develop LN, which has a significant impact on their quality of life and prognosis. Recent advances have improved the diagnostic approach to LN, and new drugs that block specific pathways and kidney damage progression have been developed. Several randomized and well-powered clinical trials have confirmed the efficacy of these agents in terms of proteinuria remission and preservation of kidney function in the medium and long term, with an acceptable safety profile and good tolerance. The combination of different therapies allows for reduction of the dose and duration of corticosteroids and other potentially toxic therapies and leads to an increase in the number of patients achieving complete remission of the disease. This consensus document carried out by the Spanish Group for the Study of Glomerular Diseases (GLOSEN) provides practical and updated recommendations, based on the best available evidence and clinical expertise of participating nephrologists.

This abridged version of the 2023 GLOSEN Consensus Document on Lupus Nephritis provides practical and up-to-date recommendations on the diagnosis, monitoring and treatment of patients with lupus nephritis (LN), including special situations such as frequently relapsing patients, refractory LN, pregnancy and thrombotic microangiopathy. These recommendations are based on the best available evidence and on the clinical experience of authors. The text is accompanied by tables and algorithms aiming to provide an easy-to-read document useful for the diagnosis and management of LN patients.

Systemic lupus erythematosus (SLE) is the paradigm of systemic autoimmune disease. A significant number of SLE patients develop lupus nephritis (LN), with serious consequences for their prognosis and quality of life. In recent years several important studies have demonstrated the efficacy of new drugs and therapeutic combinations, providing a greater precision in the definition of treatment objectives and prognostic markers.

We think that a consensus document that collects, analyzes and summarizes all this new information in an easy-to-read and practical document will be useful for a better management of LN patients. This was the objective of the present work, the complete form of which has been published previously [ 1 ].

In this summarized version we present the most important parts of the consensus document, focused on the diagnosis, definitions, objectives and treatment of the different classes of LN and some special situations. Each section includes some brief recommendations, followed by a rationale. The purpose of the tables and figures is to summarize and illustrate the content of the recommendations.

Excellent and comprehensive documents and guidelines on LN management have been published in recent years, such as the 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis [ 2 ] and the KDIGO 2021 Clinical Practice guideline for the management of Glomerular Diseases [ 3 ]. The central aims of our consensus document were to adapt the different combinations of drugs, the efficacy of which has been demonstrated in recent trials, to the different clinical profiles and special situations of LN, as well as to summarize these treatment regimens in algorithms and tables that are easy to read and translate to clinical practice. The document was prepared by Spanish Group for the Study of Glomerular Diseases (GLOSEN) nephrologists with extensive experience in the diagnosis and treatment of LN patients. Several virtual and face-to-face meetings were held for coordination, section assignments and content discussion. An exhaustive and systematic search of the literature was carried out, which included, among others, the following databases: PubMed, EMBASE, Cochrane Library, Google Scholar and ClinicalTrials.gov , as well as the abstract books of national and international congresses. Details about search strategy and levels of evidence of the selected studies are provided in the supplementary material of the complete version [ 1 ].

Recommendations

1.1. The diagnosis of SLE should be based on the characteristic signs and symptoms of the disease, according to the criteria established by the 2019 EULAR/American College of Rheumatology classification [ 4 ].

1.2. In patients with SLE, a determination of serum creatinine, estimated glomerular filtration rate (eGFR) and a urinalysis [urinary albumin/creatinine ratio (uACR) and/or urinary protein/creatinine ratio (uPCR), urinary sediment] should be performed periodically. These determinations should be more frequent (at least once or twice a year) in those patients with a higher propensity to develop LN (persistent extrarenal clinical manifestations, positivity of serological markers, early onset of SLE and non-Caucasian races).

1.3. In a significant proportion of patients, LN is asymptomatic and is detected only by analytical data. Special attention should be paid to the appearance of edema and/or de novo hypertension in SLE patients.

1.4. Kidney biopsy is needed for the diagnosis and classification of LN and should be evaluated by expert nephropathologists. It is recommended in patients with SLE and proteinuria >0.5 g/24-h (or uPCR >0.5 g/g). The presence of hematuria, leukocyturia, or urinary casts and/or unexplained impairment of renal function further reinforces the biopsy indication. Patients without proteinuria but with an active urinary sediment and/or impairment of renal function require a careful study to rule out etiologies other than SLE before performing a kidney biopsy.

LN represents one of the most frequent and serious complications of SLE [ 5–7 ]. Early diagnosis is crucial and, since LN is asymptomatic in many patients [ 8 ], periodic blood and urine analysis are recommended. A higher prevalence of atherosclerotic complications in patients with SLE has been reported [ 9 , 10 ], so regular determination of kidney function and albuminuria/proteinuria, factors that are clearly linked to an increased cardiovascular risk, are essential even in inactive lupus patients. The periodicity of these determinations must be guided by patient characteristics. The incidence of LN is higher in patients with extrarenal lupus manifestations, early onset of SLE and persistent serological markers of immunological activity (hypocomplementemia, anti-dsDNA positivity), and in non-Caucasians, so analytical determinations should be performed more frequently in such patients [ 5–7 , 10 , 11 ]. A significant proportion of patients are asymptomatic at the time of LN diagnosis. In such cases, the suspicion of LN is raised by abnormalities detected in urine and blood laboratory tests [ 12 , 13 ].

Kidney biopsy is mandatory for LN diagnosis. It is recommended in patients with SLE with persistent urinary abnormalities not attributable to other causes or with unexplained impairment of renal function [ 14–17 ]. The 2018 International Society of Nephrology/Renal Pathology Society (ISN/RPS) LN classification includes a semiquantitative analysis of active and chronic lesions having prognostic value [ 18 ]. Description of vascular and interstitial lesions should be also included [ 19–21 ]. Other lesions of considerable prognostic and therapeutic importance may also be found, such as thrombotic microangiopathy (TMA), vasculitis, podocytopathy and acute tubulointerstitial nephritis [ 15–17 ].

The histological study requires light microscopy and immunofluorescence techniques, and electron microscopy is recommended. The biopsy should be interpreted by expert nephropathologists. Figure  1 summarizes the histological classes proposed by the latest revision of the ISN/RPS [ 14 , 18 ] classification.

Indications of kidney biopsy in patients with SLE and major histological classes according to the 2018 ISN/RPS classification.

2.1. The identification, assessment and follow-up of extrarenal clinical manifestations is essential in patients with LN. The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scoring system is recommended to monitor these manifestations.

2.2. In LN patients, the amount of proteinuria (expressed as uPCR or as 24-h proteinuria), the urinary sediment, and the determination of serum creatinine and eGFR are the most important parameters to assess disease evolution and treatment efficacy.

2.3. Some factors independent of SLE activity can influence proteinuria amount, urinary sediment and kidney function, and should be carefully evaluated (Table  1 ). The amount of proteinuria does not always have a direct relationship with LN activity, especially in relapsing patients and in those with significant chronic lesions.

Main clinical factors that can influence proteinuria levels, urine sediment and kidney function independently of lupus activity.

2.4. There is no general agreement on the indications for repeating kidney biopsy in LN. It could be considered in refractory patients, in patients with sustained proteinuria to evaluate the predominance of active or chronic lesions, in some LN relapses with diagnostic or therapeutic doubts or when a condition unrelated to LN is suspected. Repeated biopsy could be also useful before the withdrawal of immunosuppression.

Monitoring of extrarenal systemic manifestations is essential in any patient with LN. The SLEDAI scoring system allows evaluation of such activity with a systematic and reproducible approach [ 22 ].

The amount of proteinuria is the most important marker for prognosis and for treatment response assessment in LN [ 23–26 ]. A precise measurement, that should be expressed as 24-h urinary protein excretion or as uPCR in an isolated urine sample, is essential. To analyze urinary sediment, automatized techniques have replaced the traditional manual techniques and have been validated for the routine monitoring of patients [ 27 , 28 ]. For eGFR calculation, the Chronic Kidney Disease Epidemiology Collaboration formula is recommended. However, not all changes in analytical parameters are related to immunological lupus activity (Table  1 ). Changes in body weight have an important influence on proteinuria. An impairment in renal function not accompanied by increases in proteinuria or changes in urinary sediment should force the physician to consider factors independent of LN activity, as well as changes in the urinary sediment without increases/reappearance of proteinuria and without changes in kidney function.

3.1. Definition of complete remission, partial remission and no response

3.1.1. The efficacy of any therapeutic strategy for LN must be evaluated by obtaining a complete remission (CR) or partial remission (PR), as defined in Table  2 .

Definitions of renal outcomes: CR, PR, non-response and relapse.

RBC/hpf: red blood cells per high-power field.

3.1.2. Time elapsed until obtaining a CR or PR is an important prognostic marker. The timeline to achieving objectives must be established according to individual patient's characteristics (Fig.  2 ). The optimal goal is to achieve CR, since long-term kidney survival is significantly better than that of patients who achieve PR alone.

Objectives in the treatment of LN. RBC/hpf: red blood cells per high-power field.

Treatment of classes I and II. CV: cardiovascular.

There is no universally agreed definitions of CR or PR, although all the guidelines coincide in proteinuria reduction and the recovery of kidney function as fundamental objectives [ 3 , 25 , 29 , 30 ]. Although normalization/increase in serum albumin is not usually included in the definitions of CR or PR, we prefer to include this parameter considering that hypoalbuminemia can be found in some patients with proteinuria levels below the nephrotic range (3.5 g/24 h) (Expert opinion). Improvement or normalization of the urinary sediment is not included within CR or PR criteria in some guidelines [ 29 ]. We prefer to maintain this criterion, since reappearance of hematuria can be a sensitive marker of clinical activity, especially in patients with residual proteinuria associated with chronic lesions. A >50% reduction in proteinuria at 6 months is associated with a better kidney survival and a proteinuria level <0.7 g/24-h at 12 months is an excellent predictor of a good long-term kidney outcome [ 23 , 24 ].

In addition to obtaining CR or PR, the time elapsed until reaching these objectives is important. The evolution of clinical and analytical parameters must be carefully evaluated at every visit, verifying their progressive improvement (Fig.  2 ). Such evolution should be adapted to the individual patient's characteristics, especially in the most aggressive forms of presentation [severe nephrotic syndrome, acute kidney injury (AKI)] [ 25 , 31 , 32 ]. In this type of patient, a slower achievement of the objectives shown in Fig.  2 can be acceptable, as long as a clear and progressive clinical and analytical improvement is evident.

3.2. Definition of relapse (flare)

Recommendation.

3.2.1. A substantial number of patients with LN present relapses after reaching CR or PR. Definition of relapse is shown in Table  2 .

The incidence of LN relapses oscillates between 10% and 50%, according to different studies. The risk is higher among patients who reach only PR and during the first years after the first episode (especially when immunosuppression is reduced or discontinued) [ 33–35 ]. However, relapses can occur at any time, even after decades of inactivity. For this reason, long-life periodic revisions are recommended in any LN patient. Most relapses are detected by the reappearance or increase in hematuria and proteinuria (Table  2 ). In the most severe cases, these changes in hematuria and proteinuria can be accompanied by a worsening of kidney function. However, it is exceptional to observe kidney function impairment not accompanied by proteinuria or urinary sediment abnormalities (hematuria, leukocyturia, red blood cell casts), so other causes of kidney function worsening not related to lupus activity should be ruled out (Table  1 ). The diagnosis of relapse is more difficult in patients with PR and in those with repeated flares of LN that have caused extensive chronic lesions and residual proteinuria. In these cases, a new renal biopsy can provide useful information about the presence of histological activity [ 36–39 ].

4.1. Classes I and II (Fig.  3 )

4.1.1. In patients with LN class I, we recommend treatment with hydroxychloroquine (HCQ), general nephroprotection and general treatment of SLE according with extrarenal manifestations.

4.1.2 In patients with LN class II with proteinuria <1 g/24-h and normal urinary sediment, we recommend same treatment as in LN class I.

4.1.3 In patients with LN class II with proteinuria >1 g/24-h despite optimal renin–angiotensin system (RAS) blockade and/or urinary sediment showing glomerular hematuria, we recommend a second assessment of kidney biopsy or to perform a new biopsy to rule out changes in histological class or a concurrent lupus podocytopathy. If class II is confirmed, we suggest adding corticosteroids and mycophenolic acid analogues (MPAA) for 6–12 months to the general treatment, with subsequent gradual tapering according to evolution. If lupus podocytopathy is found, a therapeutic approach similar to minimal change disease is suggested (see Section 4.5).

Classes I and II LN are considered mild forms of renal involvement with a good prognosis [ 40 ]. There are no controlled studies supporting a specific therapeutic regimen, although the use of HCQ is recommended. Patients with mild proteinuria (<1 g/24-h) can be managed conservatively with optimal RAS blockade [angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptors blockers (ARB) regardless of blood pressure (BP)], due to their renoprotective and anti-inflammatory effects [ 40 , 41 ].

Additionally, a strict control of BP, dyslipidemia and other cardiovascular risk factors is mandatory. It is important to keep in mind that LN classes can change over time. The presence of proteinuria >1 g/24-h despite optimized RAS blockade, with or without hematuria or kidney function impairment, should prompt the revision of kidney biopsy or the performance of a new one to rule out changes to more severe histological classes [ 36 ].

Scarce information exists about the management of patients with confirmed LN class II who maintain proteinuria >1 g/day despite optimized RAS blockade and/or glomerular hematuria. Some studies have shown favorable results of immunosuppressive treatment (corticosteroids and MPAA for 6–12 months) [ 42 , 43 ], although no controlled studies have been published.

4.2. Classes III/IV ± V: initial treatment (Fig.  4 )

4.2.1. All patients with LN classes III, IV or III/IV + V should receive corticosteroids as initial treatment (unless contraindicated) along with other immunosuppressants. As a preferred corticosteroid regimen, we suggest intravenous pulses of methylprednisolone (250–500 mg/day) for three consecutive days followed by a reduced-dose regimen (oral prednisone or equivalent 0.5–0.6 mg/kg/day).

4.2.2. In patients with proteinuria <3 g/24-h, good therapeutic compliance, infertility concerns, or contraindications or intolerance to cyclophosphamide, we suggest double initial immunosuppressive treatment with corticosteroids and MPAA [in doses equivalent to 2 g/day of mycophenolate mofetil (MMF)].

4.2.3. In cases with proteinuria <3 g/24-h, risk of therapeutic non-compliance, or contraindications or intolerance to MPAA, we suggest double initial immunosuppressive treatment with corticosteroids and intravenous cyclophosphamide (Eurolupus regimen). After the administration of the sixth pulse of cyclophosphamide, treatment with MPAA will be started (or azathioprine in case of intolerance to MPAA).

4.2.4. In those patients who have not achieved a reduction in proteinuria of at least 25% after 2–3 months of treatment with corticosteroids + MPAA or at the end of the cyclophosphamide boluses, we suggest adding belimumab to the treatment (especially if immunological activity persists), or a calcineurin inhibitors (CNI) (especially if significant proteinuria persists).

4.2.5. We suggest initial triple immunosuppressive therapy with corticosteroids + MPAA + belimumab in those patients fulfilling the profile described in recommendation 4.2.2, but presenting in addition extrarenal SLE manifestations, intense serological activity, need to rapidly reduce corticosteroids or previous LN relapses.

4.2.6. In those patients with proteinuria >3 g/24-h or complete nephrotic syndrome and fulfilling otherwise the other characteristics described in recommendation 4.2.2, we suggest initial triple immunosuppressive therapy with corticosteroids + MPAA + CNI (cyclosporine, tacrolimus, voclosporine), provided that eGFR is ≥45 mL/min/1.73 m 2 .

4.2.7. In cases with acute deterioration of kidney function, we suggest applying therapeutic schemes adapted to the patient's clinical profile (recommendations 4.2.1 to 4.2.6) but avoiding CNI in patients with eGFR <45 mL/min/1.73 m 2 .

Intravenous pulses of corticosteroids significantly improve acute inflammation and immune activity in LN [ 44 , 45 ]. There is a current trend to use lower doses of oral corticosteroids following intravenous pulses, due to the lower risk of adverse effects [ 3 , 25 , 46 ]. The Aurinia Renal Response in Active Lupus with Voclosporin (AURORA)-1 study confirmed the efficacy and safety of low-dose corticosteroid regimens, reaching 2.5 mg/day at week 12 after starting treatment [ 47 ] (Table  3 ). However, other regimens with higher doses of corticosteroids can be considered in patients with more aggressive presentations or worse responses to treatment (Table  3 ).

Recommended dose of corticosteroids for the treatment of LN. a

a Based on references [ 3 ] and [ 47 ].

i.v.: intravenous administration

MPAA represent the first line of treatment in compliant patients with proliferative or mixed LN (Fig.  4 ). As induction therapy, they show similar [ 2 , 48 , 49 ] or superior efficacy to cyclophosphamide [ 50 ], with a better safety profile. This benefit has been observed in different ethnic groups [ 51 ].

Initial treatment for classes III/IV ± V. HCQ: initial dose 4–5 mg/kg/day (maximum 400 mg daily). If eGFR <30 mL/min/1.73 m 2 , do not exceed 200 mg daily. MPAA: dose equivalent to 2 g of MMF. Cyclophosphamide: Eurolupus regimen preferred (6 biweekly i.v. pulses of 500 mg each, cumulative dose = 3 g). CNI: cyclosporine (initial dose 100–200 mg daily, blood target level 60–100 ng/mL), tacrolimus (initial dose 0.05–0.07 mg/kg/day, blood target level 4–7 ng/mL), voclosporine (23.7 mg twice daily for 1–2 years, no blood target level required). Belimumab: 10 mg/kg i.v. on days 1, 15 and 29, then every 28 days. i.v.: intravenous.

Cyclophosphamide is still a first-line therapeutic option, especially in noncompliant patients or when contraindications to MPAA exist [ 52 , 53 ]. Intravenous administration is preferred over oral route due to its lower risk of adverse effects and lower cumulative dose [ 54 , 55 ].

The Euro-Lupus Nephritis Trial, conducted in European and predominantly Caucasian patients with LN classes III, IV or V, demonstrated that low doses of cyclophosphamide (six fortnightly pulses of 500 mg each, total dose 3 g) followed by oral azathioprine, have the same clinical and immunological efficacy in the short and long term as monthly intravenous pulses with higher doses, and with a lower risk of infections [ 56 , 57 ]. Although this Eurolupus regimen was evaluated in patients with relatively preserved kidney function and without representation of other ethnic groups, it is an effective, safe and frequently used treatment in patients with proliferative LN [ 3 , 48 , 57 , 58 ].

Recent studies have shown superiority of the so-called triple immunosuppressive therapy over double immunosuppressive regimens (corticosteroids plus another immunosuppressive agent). The BLISS-LN study demonstrated that the combination of corticosteroids, belimumab, and MMF or cyclophosphamide was significantly superior to treatment with corticosteroids, MMF or cyclophosphamide and placebo in inducing CR [ 59 ]. This beneficial effect of belimumab was not observed in patients with significant proteinuria (>3 g/24-h), Black patients or those who had received cyclophosphamide. Subsequent analysis of the BLISS-LN study showed that belimumab also prevented LN relapses and slowed the loss of kidney function [ 60 ]. On the other hand, several studies have previously shown the efficacy of belimumab to control extrarenal manifestations, decrease lupus immune activity and reduce corticosteroid doses [ 61–64 ].

CNI have shown an important antiproteinuric and podocyte cytoprotective effect in different glomerular diseases, including LN [ 65 ]. Studies conducted in China showed that the combination of corticosteroids, MMF and tacrolimus was superior to corticosteroids plus cyclophosphamide in obtaining CR [ 66 , 67 ]. Prospective studies with voclosporine have shown that this drug added to corticosteroids and MMF induces CR and PR in a significantly greater number of patients than therapy with corticosteroids plus MMF and placebo, without increasing adverse effects [ 46 , 68 ]. Due to the acute and chronic nephrotoxicity that CNI (cyclosporine, tacrolimus) can induce, these agents are usually avoided (or administered with a close monitoring) in LN patients with reduced kidney function.

Although there are no studies designed in this regard, we suggest adding belimumab (especially if serological activity persists) or a CNI (especially if significant proteinuria persists) in those patients treated with dual immunosuppressive therapy without >25% reduction in proteinuria after 2–3 months of treatment.

Scarce information exists about the most effective treatments in LN patients with AKI at presentation. A post hoc analysis of the ALMS (Aspreva Lupus Management study) clinical trial compared monthly intravenous pulses of cyclophosphamide with MMF in 32 patients with eGFR <30 mL/min/1.73 m 2 at presentation [ 69 ]. The number of responses was similar (17% and 20%, respectively) and serious adverse events were more frequent in the group treated with cyclophosphamide.

4.3. Class V (membranous): initial treatment (Fig.  5 )

4.3.1. In patients with proteinuria <1 g/24-h, we suggest treatment with HCQ, general nephroprotective measures and treatment of SLE according with extrarenal manifestations.

4.3.2. In patients with proteinuria between 1.0–3.5 g/24-h, we suggest double immunosuppressive treatment with corticosteroids and CNI (tacrolimus, voclosporine, cyclosporine). If after 3–4 months of treatment a reduction in proteinuria of at least 25% has not been obtained, and especially when persistent immunological activity coexists, we suggest adding MPAA.

4.3.3. In patients with proteinuria >3.5 g/24-h or complete nephrotic syndrome, we suggest triple immunosuppressive treatment from the onset, with corticosteroids, CNI (tacrolimus, voclosporine, cyclosporine) and MPAA.

LN class V (membranous) frequently presents with nephrotic syndrome. There is a consensus regarding the indication of immunosuppressive treatment in cases with complete nephrotic syndrome. However, the management of patients with non-nephrotic proteinuria is more controversial. It seems reasonable to recommend immunosuppressive treatment in those cases who maintain proteinuria >1 g/24-h despite optimized RAS blockade [ 70 ].

Different immunosuppressive treatments have shown efficacy in class V LN, but there are no conclusive comparative studies. Corticosteroids alone are ineffective. MMPAs can induce remission but require more time to achieve therapeutic goals than CNI [ 71 ]. In patients with severe nephrotic syndrome, a more rapid and sustained reduction in proteinuria can be obtained with triple immunosuppressive therapy (corticosteroids, CNI and MPAA [ 47 , 72 ].

4.4. Classes III/IV ± V and class V maintenance therapy (Fig.  6 )

4.4.1. We suggest a low-dose scheme of corticosteroids for maintenance therapy (for example, prednisone 2.5–5 mg/day from the sixth month of treatment), although such a scheme must be adapted to the patient's characteristics. Withdrawal of corticosteroids at month 18–24 is recommended in patients with clinical and serological remission.

4.4.2. In patients achieving clinical and serological remission, we recommend a progressive and slow reduction of MPAA dose after 18–24 months of treatment. Total duration of MPAA treatment should be at least 3–5 years.

4.4.3. We recommend azathioprine (1.5–2 mg/kg/day) for those patients who do not tolerate MPAA. Dose reduction and total duration of treatment is similar to MPAA.

4.4.4. Belimumab is suggested as maintenance therapy in patients who do not tolerate HCQ and/or corticosteroids, in relapsing patients, or in those with persistent extrarenal manifestations and/or persistent serological activity.

4.4.5. In patients with LN class V initially treated with corticosteroids and CNI, reduction of corticosteroids should follow the recommendation 4.4.1. For CNI, we suggest 12–18 months of treatment followed by a gradual tapering for 6–12 months (or 12–18 months in patients with PR and significant proteinuria).

4.4.6. We recommend treatment with RAS blockers, titrating doses to achieve and/or maintain BP and proteinuria targets. If proteinuria goals are not achieved, we suggest considering the addition of sodium-glucose cotransporter-2 inhibitors (SGLT2i) (Expert opinion).

Regimens based on a reduced dose of corticosteroids have demonstrated similar efficacy to those based on higher doses, with a lower rate of side effects. When clinical and serological remission is achieved, corticosteroid withdrawal is recommended after 18–24 months of treatment, especially in patients on HCQ or another immunosuppressive agent. Intravenous cyclophosphamide in not recommended as maintenance therapy owing to the risk of severe adverse events related to excessive cumulative dose. MPAA or azathioprine have demonstrated a greater efficacy with a lower rate of side effects [ 73 ]. The ALMS study extension demonstrated that MMF was superior to azathioprine in terms of relapse prevention in patients who had achieved remission [ 74 ]. In the MAINTAIN trial, no differences in LN flares were observed between azathioprine-treated and MMF-treated patients, and the rate of adverse was similar except for hematological cytopenias, which were more frequent in the azathioprine group [ 58 ]. MPAA are preferred for maintenance therapy, although azathioprine is an effective alternative in those patients who cannot tolerate MPAA. A minimum duration of 3 years is recommended for both drugs, with a slowly progressive reduction before its complete withdrawal.

A post hoc analysis of BLISS-LN study showed that belimumab decreased the risk of relapses [ 59 , 60 ]. Therefore, belimumab is a good alternative for maintenance therapy in patients with frequent relapses, intolerance or contraindications to HCQ or persistent extrarenal manifestations.

In LN class V the optimal maintenance regimen is not well established, given the scarcity of specific studies. A randomized study in patients with classes IV and V that compared cyclosporine with azathioprine showed a similar incidence of relapses [ 75 ]. In another randomized trial, cyclosporine was associated with a higher rate of remission at 12 months than cyclophosphamide or corticosteroids, but the incidence of relapses was significantly higher among cyclosporine-treated patients [ 76 ]. MPAA and tacrolimus showed a similar efficacy as maintenance treatment in another study [ 77 ]. We suggest a slow and progressive decrease in CNI doses in patients with class V LN who have achieved clinical remission after initial therapy with CNI and corticosteroids.

Non-immunosuppressive treatment (Fig.  6 ) is extremely important during the maintenance phase. A healthy lifestyle (regular physical exercise, avoidance of overweight and smoking) as well as the control and treatment of all cardiovascular risk factors is especially important in LN patients [ 78 , 79 ]. Special attention should be paid to HCQ compliance to avoid relapses [ 80 , 81 ], as HCQ prolongs remission during immunosuppressive therapy and improves renal prognosis [ 82 , 83 ]. Treatment with RAS blockers is essential both for BP control and for achieving proteinuria goals [ 84 ]. A low-salt diet optimizes the effects of RAS blockers. There are other treatments that have demonstrated an antiproteinuric and renoprotective effect in different proteinuric kidney diseases, such as, SGLT2i, aldosterone receptor blockers, and anti-endothelin agents [ 85–88 ]. No conclusive studies have been published about their efficacy in LN, but preliminary data suggest an important antiproteinuric effect in LN patients, particularly in those with PR [ 89 , 90 ].

4.5. Lupus podocytopathy

4.5.1. We recommend a similar management to minimal change disease, including corticosteroids as the first-line therapy and CNI as the second-line in corticosteroids-resistant patients. Rituximab, cyclophosphamide, MPAA or CNI are therapeutic alternatives in corticosteroid-dependent or frequently relapsing patients.

4.5.2. In corticosteroid-resistant lupus podocytopathy with renal function impairment not otherwise explained and/or presence of glomerular hematuria, a new kidney biopsy is recommended to rule out change to a different histological class.

The pathogenesis of lupus podocytopathy is largely unknown and there are no controlled therapeutic studies. However, most of the reported cases presented with a complete nephrotic syndrome and showed a response to corticosteroids similar to that of minimal change disease [ 91–100 ]. Therefore, we recommend a therapeutic approach similar to this entity.

5.1. Refractory or resistant lupus nephritis (Fig.  7 )

5.1.1. We suggest defining refractory or resistant LN as the lack of response (or worsening of proteinuria and/or kidney function) after at least 3 months with any regimen of triple immunosuppressive therapy shown in Fig.  4 .

5.1.2. In patients whose initial treatment was based on MPAA, we suggest adding rituximab or changing MPAA to cyclophosphamide (Eurolupus regimen).

5.1.3. In refractory LN after cyclophosphamide-based initial treatment, we suggest adding rituximab or extending cyclophosphamide pulses to complete 6 months of treatment.

5.1.4. In patients with no response to 5.1.2 and 5.1.3 recommendations, we suggest treatment with new anti-CD20 drugs (obinutuzumab) or anti-plasma cell drugs (daratumumab, bortezomib), or inclusion in clinical trials with new biological drugs under evaluation.

Up to 30% of LN patients are refractory to initial treatment according to some studies [ 101 ]. It is important to consider, however, that there is no general agreement about the definition of refractory LN [ 102 , 103 ]. Before establishing this diagnosis, it is essential to rule out non-compliance, sub-optimal doses of treatment, the existence of genetic factors influencing refractoriness and, in those cases with previous LN flares, chronic histological lesions by means of a new kidney biopsy [ 36 , 37 , 104 , 105 ].

Although rituximab has not demonstrated superiority as add-on therapy to MPAA + corticosteroids [ 106 ], several observational studies including ethnically diverse patients have shown its effectiveness as rescue therapy in refractory LN [ 107–112 ].

Patients who do not respond to rituximab or extended cyclophosphamide therapy could benefit from newer anti-CD20 (obinutuzumab) or anti-plasma cell (bortezomib, daratumumab) therapies [ 113–115 ]. Cellular therapy with CAR-T cells could be an alternative for patients with LN refractory to several approaches [ 116 , 117 ]. Ideally, LN patient refractory to several lines of treatment should be included in ongoing clinical trials evaluating new therapies.

5.2. Prevention and treatment of relapses (Fig.  8 )

5.2.1. We suggest treating LN relapses according to the clinical profile of the patient, according to the algorithms shown in Figs  4 and  5 .

Initial treatment for class V (membranous). HCQ: initial dose 4–5 mg/kg/day (maximun 400 mg daily). If eGFR <30 mL/min/1.73 m 2 , do not exceed 200 mg daily. MPAA: dose equivalent to 2 g of MMF. CNI: cyclosporine (initial dose 100–200 mg daily, blood target level 60–100 ng/mL), tacrolimus (initial dose 0.05–0.07 mg/kg/day, blood target level 4–7 ng/mL), voclosporine (23.7 mg twice daily for 1–2 years, no blood target level required). CV: cardiovascular.

Maintenance treatment for classes III/IV ± V and V. CV: cardiovascular; MRA: mineralocorticoid receptors antagonists.

Recommendations and therapeutic options in refractory LN.

Prevention and treatment of relapses.

5.2.2. We recommend investigating and ensuring adequate therapeutic compliance. In cases with repeated relapses, we suggest considering a new kidney biopsy to evaluate histological activity, chronic and irreversible lesions, or changes in LN class.

5.2.3. After obtaining relapse remission, we suggest extending the duration of treatment with MPAA. In patients with repeated relapses, we suggest maintaining MPAA indefinitely at reduced doses.

5.2.4. We suggest adding belimumab to maintenance treatment in relapsing patients.

There are no studies specifically designed to compare different treatments in LN relapses. We suggest treating relapses as in the first episode, according to the patient's clinical and analytical profile (Figs  4 and  5 ). When the clinical profile advises a new cyclophosphamide course, we suggest not exceeding the total cumulative dose of 10 g. It is crucial in relapsing patients to ensure strict compliance with HCQ and with other prescribed drugs. HCQ has been associated with a lower incidence of relapses [ 80–82 ], so this drug should be prescribed indefinitely, except in cases of contraindications or intolerance. It can be difficult to differentiate residual proteinuria due to healing of previous flares from that produced by active lesions in patients with repeated relapses. In these cases, a new biopsy can provide useful information [ 36 , 39 , 118 ]. MPAA treatment could be extended beyond the 3–5 years recommended for the initial flare in relapsing patients, and it may even be recommendable to maintain low doses of MPAA indefinitely in some cases with repeated relapses. In a sub-analysis of the BLISS-LN study, belimumab reduced the risk of LN relapse by 55% [ 60 ]. Treatment with this drug may therefore be useful in relapsing patients.

5.3. Pregnancy

5.3.1. Pregnancy in LN is associated with an increased risk of maternal and fetal complications and can be planned after a minimum of 6 months of LN remission. Pregnancy in LN patients should be controlled by multidisciplinary teams within high-risk obstetric units.

5.3.2. Teratogenic or potentially deleterious drugs should be avoided. Corticosteroids, azathioprine and CNI can be prescribed when immunosuppression is required during pregnancy.

5.3.3. HCQ should be maintained to reduce the risk of LN relapse. Low aspirin dose (100 mg/day) should be prescribed before the 12th week of pregnancy to reduce the risk of pregnancy complications.

The risk of hypertension, preeclampsia, prematurity and preterm delivery is increased in LN patients. Pregnancy in any LN patient must be carefully planned and requires at least 6 months of remission to decrease the risk of relapse [ 119–121 ]. The first episode of LN can occur in pregnant SLE patients; a renal biopsy can be performed after the 20th week of pregnancy, provided there are no contraindications [ 122 , 123 ]. The differential diagnosis between preeclampsia and LN flare is challenging; however, the evaluation of several clinical, laboratory, and imaging data is useful to establish the right diagnosis [ 124–126 ] (Table  4 ).

Differential diagnosis of LN flare and preeclampsia/HELLP in pregnant women.

HELLP: Hemolysis, Elevated Liver enzymes, Low Platelets; PIGF: placental growth factor; SFlt-1 (or sVEGFR-1): soluble fms-like tyrosine kinase-1; US: ultrasonography.

The prescription of low doses of aspirin before the 12th week of pregnancy reduces the risk of preeclampsia and intrauterine growth retardation. HCQ should be maintained during pregnancy, unless contraindicated, in order to decrease the risk of SLE flares and LN relapses [ 16 , 82 , 127–129 ].

Cyclophosphamide and MPAA are contraindicated in pregnancy due to their teratogenic effects. Rituximab can cause B cell depletion and neutropenia in the fetus and newborn, increasing the risk of infection. When immunosuppression is required during pregnancy (to treat either a first LN outbreak or an LN relapse, or as maintenance therapy in patients at high risk for relapse), corticosteroids, azathioprine and CNI can be used (Table  5 ).

Use of immunosuppressive drugs during pregnancy in patients with LN.

5.4. Thrombotic microangiopathy

5.4.1. In patients with LN and concomitant TMA, determination of antiphospholipid antibodies and ADAMST-13 activity should be performed. Although immunosuppressive treatment of LN alone can resolve LN-related TMA in some cases, the addition of anticoagulant therapy, plasma exchange or complement blockers may be indicated depending on the underlying abnormalities detected.

LN patients, especially those with classes III/IV ± V, can present TMA lesions on renal biopsy. In some cases, these lesions are accompanied by the typical hematological manifestations of TMA (microangiopathic hemolytic anemia with schystocytes and low serum haptoglobin, thrombocytopenia). The etiology of LN-associated TMA is variable: deposition of immunocomplexes in the microvascular walls can cause endothelial damage severe enough to trigger TMA. In these cases, treatment will consist of the immunosuppressive approaches discussed for LN classes III/IV ± V. Some SLE patients develop antibodies against ADAMTS-13, a protein that prevents the aggregation of von Willebrand factor multimers. When ADAMTS-13 activity is less than 5%–10% of normal, the diagnosis of thrombotic thrombocitopenic purpura (TTP) can be established [ 130 ]. The PLASMIC score has demonstrated its usefulness in situations in which the determination of ADAMTS-13 is not possible [ 131 ]. In LN-related TTP, the addition of plasma exchange to immunosuppressive treatment can facilitate the recovery of renal function and improvement of renal lesions.

Up to 30%–40% of SLE patients present antiphospholipid antibodies and can develop antiphospholipid syndrome (APS), an important risk factor for vascular and renal damage in SLE [ 21 , 132–137 ]. In addition to a high risk for arterial and/or venous thrombosis, APS can also cause the so-called APS-associated nephropathy, with renal lesions very similar to those of TMA, in addition to renal artery stenosis [ 137 , 138 ]. While immunosuppression by itself does not induce favorable effects in APS, long-term anticoagulation is the treatment of choice in APS [ 139 , 140 ]. Finally, some patients with LN-related severe TMA have been treated with complement blockers such as eculizumab, with variable results [ 141–149 ]. Although some cases may present mutations in complement regulatory genes [ 149–151 ], several studies have shown a transient complement activation in TMA of different etiologies, without identifiable genetic abnormalities [ 152 ]. These findings could support the temporary use of complement blockers in LN-related TMA unresponsive to immunosuppressive therapy [ 153 , 154 ], although controlled prospective studies are needed.

The objectives in the treatment of patients with LN go beyond renal remission. SLE is a chronic inflammatory and autoimmune disease that affects different organs and systems. Immune dysfunction and accelerated atherosclerosis are key conditions associated with SLE and LN [ 2 , 4 , 9 , 10 ]. The development of chronic kidney disease, with progressive deterioration of renal function and persistent proteinuria, added to the short- and long-term adverse effects of anti-inflammatory and immunosuppressive drugs, has a significant impact on the development of acute and chronic complications. Among other things, LN patients have a greater susceptibility to infections and neoplasms, cardiovascular events, metabolic disturbances, involvement of the musculoskeletal system and bone, cutaneous and ocular damage, and infertility, with important deleterious consequences on quality of life and life expectancy [ 155 ]. Therefore, the prevention and appropriate treatment of all these complications within a holistic and multidisciplinary approach, is essential. Supplementary data, Tables S1 and S2 summarize the most common general recommendations to avoid these risks.

The authors of this document would like to thank the support and collaboration of the Carlos III Health Institute (ISCIII), the RICORS2040 program (RD21/0005/0001) financed by the European Union (European Union—Next Generation EU), Mechanism for the Recovery and Resilience (MRR) and especially the support of the GLOSEN working group members.

All authors participated in the regular consensus meetings, developed at least one specific section of the main document, including search and literature review, and approved and signed the final document, including tables and figures and the supplementary material before submission. M.P. carried out the design and general coordination of the study. M.P. and J.E.R.-R. designed and performed the main and supplementary figures and the correction, editing and layout of the main and supplementary tables . J.E.R.-R. and C.G.-C., in addition to their specific sections in the main document, performed the final general editing of the manuscript.

J.E.R.-R.: paid lectures and consultancy for GSK, Otsuka and Alexion. C.G.-C.: paid lectures and consultancy for AstraZeneca, Esteve, Novonortis, Boehringer Ingelheim, Astellas, Otsuka, Novartis, Mundifarma, Baxter and Vifor. A.I.Á.: nothing to disclose. M.Espino: paid lectures for Alexion. M.Espinosa: paid lectures and consultancy for Alexion. G.F.-J.: paid lectures for GSK and Otsuka. X.F.: paid consultancies for Otsuka and Novartis. M.G.: paid lectures and consultancy for GSK. M.M.: nothing to disclose. E.M.: paid lectures for GSK. L.F.Q.: paid lectures for GSK and Otsuka. M.P.: paid lectures and consultancy for GSK, Osuka, Novartis, Apellis, Alexion, Sanofi, Vifor and Travere.

The data underlying this article are available in the article and in its online supplementary material .

Rojas-Rivera JE , García-Carro C , Ávila AI et al.  Documento de consenso del Grupo de Estudio de Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN) para el diagnóstico y tratamiento de la nefritis lúpica . Nefrologia 2023 ; 43 : 6 – 47 . https://doi.org/10.1016/j.nefro.2022.10.005 .

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Author notes

• proteinuria
• immunosuppressive agents
• adrenal corticosteroids
• systemic lupus erythematosus
• glucocorticoids
• lupus nephritis
• renal glomerular disease
• mineralocorticoids
• renal biopsy

Supplementary data

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Lupus and Lupus Nephritis. What’s the Connection?

May 24, 2022

It’s time to shine a light on a little talked about but common result of systemic lupus-lupus nephritis . 

• Lupus affects 1.5 million adults in the U.S.
• In adults with lupus, 50% will have kidney disease
• Between 1 and 3 out of every 10 people with lupus nephritis will develop kidney failure

Download the lupus nephritis fact sheet . 

What is lupus?

Lupus is an autoimmune disorder, meaning it is caused when the immune system turns against the body. There is no clear cause of lupus; however, family history, infections or viruses, and environmental factors like toxic chemicals or pollution, may play a role. 

There are two main types of lupus:

• Systemic lupus erythematosus (SLE): This form can cause harm to the skin, joints, kidneys, and brain. 
• Discoid lupus erythematosus: Discoid lupus only affects the skin. 

How does lupus cause kidney damage?

People with lupus experience swelling, and in some cases, this inflammation extends to the kidneys. If this happens, the small filters in the kidneys, called glomeruli , become damaged and can’t filter out wastes properly. 

Learn more about lupus and your kidneys .

How do I know if I have lupus or lupus nephritis?

There are no standard tests to diagnose lupus symptoms vary from person to person. If lupus is suspected, a rheumatology specialist will often get involved to confirm the diagnosis.  

To determine whether or not you have lupus nephritis, your doctor will review your medical background, family history, and symptoms, including:

• Blood in the urine ( hematuria ): Your kidneys are supposed to stop blood cells from getting into your urine – if this occurs, your urine may look pink or light brown from blood
• Proteinuria or higher than normal levels of protein in the urine 
• Swelling due to fluid buildup in the ankles, legs, or eyes
• Unexplained weight gain
• High blood pressure
• Inflammation or scarring of the kidneys

Doctors may request urine samples to test for protein and blood, blood tests to determine eGFR , and a kidney biopsy . 

Learn more about testing .

Treating lupus and lupus nephritis

Since the body’s immune system is attacking the body, drugs like steroids and antimalarials are used to block the body’s immune system. However, everyone is unique, which means a combination of therapies may be needed to manage symptoms, including:

• Corticosteroids and immunosuppressive drugs: These drugs help calm the immune system down.
• Monoclonal antibodies: Artificial proteins that work as antibodies against one specific substance. 
• ACE inhibitors and ARBs: Blood pressure medication helps reduce protein loss through urine.
• Diuretics: Helps remove excess fluid.
• Diet change: Some diet changes may be needed to take some burden off the kidneys. For example, following a diet low in sodium, fat, and protein helps manage blood pressure to help prevent long-term kidney damage.

Your doctor will help you find a treatment plan that is right for you . 

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Complement 3 glomerulopathy (c3g), chronic kidney disease – associated pruritus (itchy skin), how is high blood pressure treated, stage 3b chronic kidney disease (ckd), urinary tract infections, stage 4 chronic kidney disease (ckd), complement 3 glomerulopathy (c3g): knowing the signs and symptoms, minimal change disease, hydronephrosis, related news and stories.

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Clinical outcomes in lupus nephritis patients treated with belimumab in real-life setting: a retrospective comparative study in China

1 Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China

2 Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China

3 Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China

Bingjing Jiang

Wenfeng wang, caiming chen, jianxin wan, associated data.

The following information was supplied regarding data availability:

The raw data is available in the Supplementary Files .

The use of belimumab in treating lupus nephritis (LN) patients in China is still in its early stages. This retrospective comparative study aims to delineate the disease activity, associated therapies, clinical outcomes, and adverse events among LN patients treated with belimumab, reflecting real-world experience in southeastern China.

From May 2020 to December 2023, 54 LN patients treated with belimumab and 42 LN patients treated with conventional therapy were enrolled. All patients had a follow-up period of more than 3 months. The general information, presenting clinical and laboratory data, and outcomes were collected and compared.

At 3 months of belimumab treatment, compared to baseline, there was a decrease in proteinuria from 74.1% to 64.8% ( p  < 0.001), a reduction in hematuria from 59.3% to 37.0% ( p  = 0.008), and an increase in partial or complete renal response from 53.7% to 75.9% ( p  < 0.001). The median SLEDAI score decreased from 10 to 5 ( p  < 0.001), and the proportion of patients achieving low lupus disease activity state (LLDAS) increased from 11.11% to 16.67% ( p  < 0.001) by the 3-month evaluation. Notably, there were significant reductions in oral corticosteroid dosages, with a median decrease from 30 to 17.5 mg/day ( p  < 0.001) by 3 months, and the proportion of patients requiring >5 mg/day of steroids decreased from 88.89% at baseline to 79.07% at six months ( p  < 0.001). Compared to the conventional therapy group, the belimumab group experienced a significant reduction in median steroid dosage and increased the proportion of patients achieving remission or LLDAS. The incidence of treatment-emergent adverse events (TEAEs) was significantly lower in the belimumab group (29.6% vs 52.4%, p  = 0.024).

These findings support the potential of belimumab to improve renal and serological parameters, reduce disease activity, lessen corticosteroid dependence, and decrease the risk of TEAEs, demonstrating its safety and efficacy as an adjunct therapy in LN management.

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting various tissues, from the skin to internal organs ( Anders et al., 2020 ). Lupus nephritis (LN), one of the most severe and common manifestations of SLE, develops in 40–60% of SLE patients in the early stages. This manifestation is notably more prevalent among Chinese patients and imposes a significant economic burden ( Feng et al., 2011 ). Pathologically, LN is characterized by the deposition of immune complexes within the endothelial and subendothelial layers of the affected kidneys, resulting in extensive damage and nephron loss during the acute phase. Without effective treatment, LN can lead to irreversible structural or functional damage. Renal involvement serves as an independent risk factor for a poor prognosis in patients with SLE, associated with prolonged hospitalization and increased mortality rates ( Feng et al., 2011 ; Davidson et al., 2018 ; Tanaka et al., 2018 ). The management of LN typically requires long-term steroids and immunosuppressive therapy to control disease activity and preserve kidney function. However, the remission rate among LN patients remains unsatisfactory, with approximately 10–20% progressing to end-stage renal disease ( Yu et al., 2022 ). Timely disease management significantly increases the 10-year survival rate from 46% to 95%, highlighting the critical importance of early recognition and intervention in LN ( Chen et al., 2008 ).

B cells, the precursors to plasma cells responsible for antibody production, play a pivotal role in the pathogenesis of SLE. In 2011, belimumab, a biologic agent, received approval for treating patients with active SLE. This recombinant human monoclonal antibody targets the soluble B-lymphocyte stimulator, a key regulator of B lymphocyte function, offering a novel approach to SLE management ( Hahn, 2013 ; Scholz et al., 2008 ). The last decade has seen belimumab emerge as a significant regulator in SLE treatment, as evidenced by numerous clinical studies ( Levy et al., 2021 ). Notably, a landmark two-year study involving 448 LN patients demonstrated that adjunctive belimumab treatment resulted in significantly improved primary efficacy renal responses compared to standard therapy alone ( Furie et al., 2020 ). This enhancement in treatment outcomes was further supported by a recent observational study, underscoring belimumab’s benefit when added to standard therapy in LN patients ( Sishi et al., 2023 ). Additional real-world studies have corroborated these findings, showing that belimumab reduces disease activity, flare rates, and oral glucocorticoid dose in LN patients ( Roberts et al., 2023 ; Tan et al., 2023 ). The drug’s safety and efficacy have been validated in specific patient populations, including children, those undergoing dialysis, and post-transplant patients, broadening its applicability ( Tan et al., 2023 ; Liu et al., 2022 ; Binda et al., 2020 ). Despite these positive outcomes, caution is warranted due to the association of belimumab with various adverse reactions, including infections, acute pancreatitis, and myositis ( Tan et al., 2023 ; Wise & Stohl, 2019 ). Moreover, the safety and efficacy of belimumab in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m 2 remain to be fully determined, highlighting an area for further research.

Therefore, belimumab treatment emerges as a promising strategy for disease modification in LN. However, further investigation is imperative to confirm its safety and efficacy, particularly among Chinese patients with LN. This study aims to evaluate the clinical efficacy and safety of belimumab in LN patients within a real-life setting, providing crucial insights into its application and outcomes in this demographic.

Methods and Materials

Patient selection.

Between May 2020 and December 2023, patients at the First Affiliated Hospital of Fujian Medical University, who were undergoing combined therapy with belimumab and had a follow-up period of at least three months, were enrolled in the belimumab group. Patients who received conventional therapy during the same timeframe and underwent routine follow-up were enrolled in the conventional therapy group. At the time of enrollment, these patients in the belimumab group were administered belimumab for the first time. The diagnosis of SLE adhered to the SLICC/ACR SLE classification criteria or the revised 1997 American College of Rheumatology criteria. The confirmation of LN was based on renal biopsy results or sustained positive findings in urine analysis ( DIGO, 2021 ; Tiao et al., 2016 ; Hochberg, 1997 ). Patients with less than three months of follow-up were excluded from the study.

This study was performed in accordance with the Helsinki Declaration and approved by the ethics committee of the First Affiliated Hospital of Fujian Medical University [2015]084-2. Written informed consent was obtained from each patient.

Data collection

Clinical data were retrieved from patients’ medical records upon hospitalization, encompassing the course of SLE and LN, clinical manifestations, age, gender, and the initial immunosuppressive regimen combined with belimumab. Biological data comprised serum creatinine levels, complete blood counts, complement 3 (C3), complement 4 (C4), anti-dsDNA antibodies, 24-hour proteinuria, urinary albumin/creatinine ratio (UACR), proteinuria, hematuria, leukocyturia, cylindruria, and the proportion and absolute count of CD19 + B cells. SLEDAI-2K scores were recorded to evaluate clinical disease activity ( Gladman, Ibañez & Urowitz, 2002 ). Renal biopsy specimens were evaluated using light microscopy, direct immunofluorescence, and electron microscopy. Information on concomitant therapeutic agents, daily glucocorticoid dosage, and adverse events (AEs) was gathered. Patients received regular follow-ups, and data corresponding to month 3, month 6, and month 12 were collected for analysis.

Definitions

Complete renal response (CRR) was defined as proteinuria less than 0.5g/24 h or 50mg/mmol, accompanied by improvement or stabilization in renal function (at least normal or no worse than 10% below baseline). Partial renal response (PRR) was defined as proteinuria less than 3.0g/24 h with a reduction of more than 50% from baseline, along with improvement or stabilization in renal function ( DIGO, 2021 ).

Patients were considered to be in remission if they met the following criteria: clinical SLEDAI-2K score = 0 (serology excluded), PGA score <0.5, and receiving an equivalent glucocorticoid dose of ≤5 mg/d with stable antimalarials, immunosuppressive therapies, and biological agents, in accordance with the recommendations of the DORIS Task Force ( Van Vollenhoven et al., 2021 ). Lupus Low Disease Activity State (LLDAS) is defined as SLEDAI-2K ≤4, inactivation of central organ system, PGA score ≤ 1.0, absence of new activity, steroids dosage ≤7.5mg/day, and standard dosages of antimalarial drugs, immunosuppressants, and biological agents ( Tselios, Gladman & Urowitz, 2019 ). Based on a previous study, disease severity subgroups were categorized according to SLEDAI scores: mild (0–6), moderate (7–12), and severe (>12) ( Liu et al., 2022 ).

Belimumab therapy

Belimumab administration followed recommended guidelines ( Ward & Tektonidou, 2020 ). Briefly, patients received 10 mg/kg of belimumab on day 1, 15, and 29, and then received the same dose every 28 days. Vital signs of patients were monitored during infusion using an electrocardiogram monitor.

Statistical analysis

Statistical analysis was performed using SPSS 27.0 (SPSS, Chicago, IL, USA) and GraphPad version 8.3.0 (GraphPad Software, San Diego, CA, USA). The Shapiro–Wilk test was used to assess the normality of the data. Continuous variables with normal distribution were presented as mean ± standard deviation (SD), and the paired t test was used for comparison within the same group. The continuous variables with non-normal distribution were described by median with interquartile range (IQR), and the Wilcoxon Signed-Rank Test was used for comparison within the same group, while the Mann–Whitney U Test was used for comparison between groups. Categorical variables were expressed as percentages and compared using the χ 2 test or Fisher exact test. A p -value <0.05 was considered statistically significant.

Patient characteristics and indications for initiation of belimumab

A total of 96 patients were enrolled in this study, comprising 54 in the belimumab group and 42 in the conventional therapy group. Among the individuals receiving belimumab therapy, all had used it for at least 3 months, 43 for 6 months, and 18 for 12 months. The primary objectives for initiating belimumab treatment included controlling active SLE or LN in 83.3% of cases, reducing steroid dependence in 11.1%, and preventing disease flares in 5.6%. As delineated in Table 1 , in terms of follow-up duration, the belimumab group had a significantly shorter duration compared to the conventional therapy group (7 months vs 37 months, p <0.001). Demographically, the median age in the belimumab group was 37 [23.25, 45] years, with 87.0% (47/54) females. No significant differences were found between two groups.

Among the cohort, 92.7% (89/96) had renal biopsy-confirmed LN, with Class IV being the most common. As shown in Table 1 , there was no significant difference in renal pathology types between the two groups. The SLEDAI score of the belimumab group was 10 [5.25,16], the median PGA score was 1.85 [0.92, 2.3], with a remission rate of 9.3% (5/54), and the median proteinuria level was 1.48 [0.18, 3.36] g/24 h, and the median serum creatinine level was 65.0 [53.0, 77.25] µmol/L, showing no significant difference from the conventional therapy group.. Notably, 4 (7.4%) of the patients in the belimumab group were undergoing renal replacement therapy, with one receiving peritoneal dialysis and three undergoing hemodialysis, whereas the conventional therapy group had none. Additionally, nine patients had an eGFR less than 30 mL/min/1.73 m 2 , a category previously excluded from randomized controlled trials ( Furie et al., 2020 ). In the belimumab group, anti-dsDNA antibodies were positive in 63.0% (34/54) of patients, 90.7% (49/54) had low C3 levels, and 75.9% (41/54) had low C4 levels. No significant differences were found between two groups.

Upon enrollment, all patients were on steroid therapy. As shown in Table 1 , in the belimumab group, the median prednisone equivalent dose was 30 [10, 50] mg/day, while in the conventional therapy group, it was 40 mg/day [30, 50]. The difference was not statistically significant ( p =0.054). In the belimumab group, 88.9% (48/54) of patients were treated with hydroxychloroquine, 55.6% (30/54) received mycophenolate mofetil, 14.8% (8/54) were given tacrolimus, and 9.3% (5/54) were administered multitarget therapeutics. No significant differences were found between the two groups.

Renal manifestations

The majority of patients exhibited an improvement in renal function, as evidenced by evaluations of serum creatinine, hematuria, proteinuria, leukocyturia, cylindruria, and the UACR, which were conducted regularly throughout the study.

Notably, as shown in Table 2 , in belimumab group, the UACR showed a significant reduction from 654.42 [29.52, 1943.18] mg/mmol at baseline to 210.00 [18.35, 961.52] mg/mmol by month 3 ( p = 0.008), with a further decrease to 109.25 [22.60, 336.11] mg/mmol by month 6 ( p = 0.056). Additionally, the proportion of patients presenting with proteinuria declined from 74.1% (40/54) at baseline to 64.8% (35/54, p <0.001) at month 3, 60.5% (26/43, p <0.001) at month 6, and 55.6% (10/18, p = 0.023) at month 12. Among the patients with hematuria at baseline (59.3%), the prevalence decreased to 37.0% (20/54), 27.9% (12/43), and 11.1% (2/18) by month 3, 6, and 12, respectively ( p = 0.008, p <0.001, p = 0.529). Baseline assessments indicated that 53.7% (29/54) of the participants had already achieved either partial renal remission (PRR) or complete renal remission (CRR), as shown in Fig. 1 . Their use of belimumab was intended to facilitate a reduction in corticosteroid utilization. By month 3, 27.8% (15/54) and 48.1% (26/43) attained CRR and PRR, respectively. Remarkably, by month 6, 95.3% (41/43) achieved either PRR or CRR, and by month 12, all 18 assessed patients (100%) reached either PRR or CRR. No renal flares were reported during the study.

At baseline, 29 patients (53.7%) achieved CRR or PRR. At month 3, 15 (27.8%) and 26 (48.1%) patients achieved CRR and PRR. At month 6, 15 (34.9%) and 26 (60.5%) patients achieved CRR and PRR. At month 12, 9 (50.0%) and 9 (50.0%) patients achieved CRR and PRR. CRR, complete renal response; PRR, partial renal response.

In comparison, there were no significant differences in UACR, proteinuria, hematuria, leukocyturia, and serum creatinine at month 3, month 6, and month 12 in two groups ( Table 3 ).

Serologic features

As delineated in Table 2 , the prevalence of positive anti-dsDNA antibodies among patients in belimumab group diminished over time: from 34 (62.96%) at baseline to 15 (27.77%, p = 0.129) at month 3, and further reducing to 14 (32.56%, p = 0.015) at month 6, as illustrated in Fig. 2A Additionally, a statistically significant reduction was observed in the percentage of CD19 + B cells at 3, 6, and 12 months post-treatment, compared to baseline levels ( p <0.001 at 3 and 6 months, p = 0.013 at 12 months), depicted in Fig. 2B . The number of patients with a low C3 level decreased from 49 (90.7%) at baseline to 44 (81.5%) at 3 months, 36 (83.7%) at 6 months, and 16 (88.9%) at 12 months ( p = 0.039 at 3 months, p = 0.302 at 6 months, and p = 0.111 at 12 months). Similarly, the patient count with low C4 levels showed a reduction from 41 (75.9%) initially to 34 (63.0%) at 3 months, 27 (62.8%) at 6 months, and 12 (66.7%) at 12 months ( p <0.001 at 3 and 6 months, p = 0.025 at 12 months). Figures 2C and ​ and2D 2D indicate that the levels of C3 and C4 after 3, 6, and 12 months of belimumab treatment were significantly elevated compared to baseline values.

(A) Anti-dsDNA antibody positive rate (%). (B) Percentage of CD19+ B cells (%). (C) Complement 3 level (g/L). (D) Complement 4 level (g/L). * p  < 0.05; ** p  < 0.01; *** p  < 0.001.

In comparison, at month 6 and month 12, the C3 levels in the belimumab group were lower than those in the conventional therapy group (0.66 g/L vs 0.76 g/L, p =0.02), (0.60 g/L vs 0.75 g/L, p =0.015), as shown in Fig. 3A . Additionally, at month 12, the proportion of patients with low C3 level in the belimumab group was higher than those in the conventional therapy group (88.6% vs 61.9%, p =0.037). During the follow-up period, there were differences in the prevalence of positive anti-dsDNA antibodies, IgM levels, IgG levels, C4 levels, and the proportion of low C4 level, between the two groups, but these differences were not statistically significant.

(A) Complement 3 level (g/L). (B) Dosage of oral steroid (mg/d). (C) SLEDAI score. (D) Remission rate (%). * p  < 0.05; ** p  < 0.01; *** p  < 0.001.

Steroid dose

At the commencement of the study, all 96 participants were prescribed steroids. In belimumab group, a significant reduction in the median steroid dose was observed: 30 [10, 50] mg/day at baseline to 17.5 [10, 25] mg/day by 3 months, 10 [7.5, 15] mg/day by 6 months, and 10 [5, 10] mg/day by 12 months ( p  < 0.001 at each time point). At baseline, 85.19% (46/54) of patients required steroid doses exceeding 7.5 mg/day. This proportion decreased to 83.33% (45/54, p  < 0.001) by 3 months and further to 72.09% (31/43, p  < 0.001) by 6 months. Similarly, the percentage of patients prescribed more than 5 mg of steroids daily decreased from 88.89% (48/54) initially to 87.04% (47/54, p  < 0.001) by 3 months and 79.07% (34/43, p  < 0.001) by 6 months, as illustrated in Figs. 4A and ​ and4B 4B .

(A) The oral prednisone equivalent daily dose of glucocorticoids significantly decreased from baseline to month 3, month 6, and month 12 ( p  < 0.001). (B) The proportion of patients taking steroids above 5 mg or 7 mg per day had significantly decreased. (C) Disease severity subgroups based on SLEDAI score in the cohort. (D) The treatment goals achieved in our cohort. LLDAS, Lupus Low Disease Activity State.

As shown in Table 3 and Fig. 3B , in comparison, at month 3, the steroid dose in the belimumab group was significantly lower than in the conventional therapy group (17.5 mg/d vs 25.0 mg/d, p = 0.009). At month 6 and month 12, the steroid doses in the belimumab group were lower than in the conventional therapy group, but the differences were not statistically significant. During the follow-up period, the proportion of patients in the conventional therapy group requiring more than 7.5 mg or 5 mg of steroids daily decreased, with no statistically significant differences when compared to the belimumab group.

Assessment of overall clinical response and disease activity

In belimumab group, the median SLEDAI score exhibited a significant reduction from an initial value of 10 [5.25, 16] to 5 [2, 8] at 3 months, 4 [2, 6] at 6 months, and maintained at 4 [2, 6] at 12 months ( p  < 0.001 at each time point). Prior to belimumab treatment, 23 patients (42.6%) were classified within the severe category, while 14 patients (25.9%) were deemed to have moderate disease severity. Following the treatment with belimumab, there was a significant reduction in the proportion of patients classified as severe, with the majority showing improvements in SLEDAI scores, as shown in Fig. 4C . At the commencement of belimumab therapy, remission was observed in 9.3% (5/54) of the patients. Subsequent evaluations revealed an increase in the number of patients in remission to 7 (13.0%, p  < 0.001) at 3 months, 9 (20.9%, p  < 0.001) at 6 months, and 5 (27.8%) at 12 months. Concurrently, the number of patients achieving LLDAS escalated from 6 (11.10%) at baseline to 9 (16.67%, p  < 0.001) at 3 months, 11 (25.58%, p = 0.003) at 6 months, and 7 (38.89%, p = 0.389) at 12 months, as shown in Fig. 4D .

In comparison, at month 6, the SLEDAI scores of patients in the belimumab group were significantly lower than those in the conventional therapy group (4 vs 6, p = 0.014), and the number of patients achieving remission in the belimumab group was significantly higher than in the conventional therapy group (9 vs 2, p = 0.026), as depicted in Table 3 , Figs. 3C and ​ and3D. 3D . Additionally, at month 3 and month 6, the PGA scores of patients in the belimumab group were significantly lower than those in the conventional group,(0.95 vs 1.0, p = 0.026), (0.8 vs 1.0, p = 0.004).

Treatment-emergent adverse events

Throughout the entire follow-up period, as detailed in Table 4 , the majority of treatment-emergent adverse events (TEAEs) were infections of a mild nature, comprising 13 cases of urinary tract infection, 14 cases of respiratory tract infection, three cases of herpes zoster, and one case of gastrointestinal infection. Moreover, six patients reported nervous system disorders, two cases occurred in psychiatric disorders, and another associated with musculoskeletal discomfort. The TEAEs were predominantly mild to moderate in severity and were ameliorated through symptomatic management. Throughout the study, no instances of mortality were observed.

Notably, the incidence of TEAEs in the belimumab group was significantly lower than in the conventional therapy group (29.6% vs 52.4%, p = 0.024). Particularly significant was the reduced incidence of respiratory tract infections in the belimumab group, which was notably lower (7.4% vs 23.8%, p = 0.049).

Despite significant therapeutic advancements, some LN patients fail to achieve CRR, leading to a poor long-term prognosis. Moreover, even for those who do achieve CRR, long-term therapy with steroids and immunosuppressants can result in numerous treatment-related adverse effects, some of which may be life-threatening ( Ji et al., 2022 ). Belimumab, a promising biologic agent, is recommended for patients with inadequate response to standard treatment, with the goal of achieving renal remission, reducing flare and decreasing steroid dosage ( Furie et al., 2020 ; Fanouriakis et al., 2019 ). However, in clinical practice, meeting the eligibility criteria of clinical trials can be challenging for patients. For instance, the efficacy of belimumab in patients undergoing renal replacement therapy remains unclear. Therefore, more real-world studies are warranted. This study analyzed the baseline characteristics and outcomes of LN patients receiving conventional therapy and add-on therapy with belimumab, with the aim of evaluating and comparing the real-world efficacy and tolerability of add-on therapy with belimumab. The adjunctive therapy with belimumab conferred benefits in terms of renal response and a reduction in steroid dosage. Additionally, our research demonstrated the safety of belimumab in treating LN.

In our study, both groups exhibited a significant reduction in the proportion of patients experiencing hematuria, cylindruria, proteinuria, and leukocyturia. Additionally, renal function was noted to remain stable during the follow-up period. Consistent with findings from previous studies, the addition of belimumab to standard treatment for LN patients resulted in an overall improvement in clinical response and disease activity ( Tan et al., 2023 ; Yu et al., 2023 ; Navarra et al., 2011 ; De Oliveira et al., 2020 ). Serological parameters indicated that patients with abnormal levels at baseline showed improvement towards normal levels, which persisted throughout the treatment process, including anti-dsDNA antibodies, C3, and C4.

Notably, approximately ninety-five percent of our patients who received add-on therapy with belimumab achieved partial or complete renal response at their last visit, accompanied by a significant increase in the proportion of patients achieving LLDAS and remission. It is noteworthy that all six LN patients who received belimumab in addition to conventional therapy presenting with acute kidney injury (AKI) experienced varying degrees of recovery in renal function. However, among the three patients with AKI who received conventional therapy only, one patient’s kidney function never recovered during the follow-up period and eventually started peritoneal dialysis. Furthermore, compared with conventional therapy, belimumab therapy led to a more rapid reduction in the daily dosage of steroids. Additionally, most patients with normal serological markers did not experience deterioration, highlighting the crucial role of belimumab in preventing disease flare, a finding consistent with other observational studies ( Sishi et al., 2023 ; Tan et al., 2023 ). Indeed, no renal flares were observed in our cohort.

As a complement to randomized controlled trials, our study encompassed a broader spectrum of LN patients, including those at stages 4 and 5 chronic kidney disease, individuals undergoing hemodialysis or peritoneal dialysis, and patients who had previously received rituximab before initiating belimumab treatment. Belimumab appears to offer additional benefits for LN patients undergoing kidney replacement therapy. This finding is consistent with the study by  Liu et al. (2022) which reported that belimumab, when combined with conventional therapy, improved serological features and reduced disease activity in LN patients undergoing dialysis. Similarly,  Binda et al. (2020) demonstrated that adjunctive therapy with belimumab could prevent immunologic flare in LN patients receiving peritoneal dialysis or following kidney transplantation. Our study corroborated these findings. In our belimumab group, three patients were undergoing hemodialysis, and one patient was undergoing peritoneal dialysis. Following belimumab treatment, these patients exhibited increases in complement levels, seroconversion of anti-dsDNA antibodies, and reductions in steroid dosage.

Our study also demonstrated that belimumab exerts a glucocorticoid-reducing effect in patients with LN, consistent with findings from previous studies on SLE patients. This effect can lead to a reduction in the duration and average dose of steroid treatment. Specifically, at month 3, the steroid dosage was decreased in 36 out of 54 patients receiving add-on therapy with belimumab. However, it is notable that none of the patients completely discontinued steroids in our study, regardless of whether belimumab was added to the conventional therapy, possibly due to our conservative treatment approach. In contrast, a study from Italy reported that 35% of their patients receiving belimumab as adjunctive therapy discontinued steroids indefinitely, while the steroid dosage in other patients was reduced to approximately 40% of the baseline ( Binda et al., 2020 ). Similarly, a real-world report by  Tan et al. (2023) demonstrated that 8.0% of patients receiving belimumab treatment discontinued steroids altogether, while 77.0% experienced a reduction in dosage. Sishi et al. (2023) conducted a retrospective analysis involving 112 patients receiving belimumab in combination with conventional therapy, compared to 112 matched control patients receiving conventional therapy only. They found that combination therapy with belimumab effectively reduced steroid dosage, although no significant difference was observed between the two groups ( Sishi et al., 2023 ). These findings align with the results of our study, where combination therapy with belimumab effectively reduced the steroid dosage.

Furthermore, in line with previous studies, our findings also indicate that patients generally exhibit good tolerance to belimumab ( Sishi et al., 2023 ; Tan et al., 2023 ; Liu et al., 2022 ; Shipa et al., 2021 ). The most common TEAEs observed in our belimumab group were infections, primarily urinary tract infections. It is important to note that these infections cannot be solely attributed to belimumab, as patients were concurrently receiving steroids and immunosuppressants, which can also increase susceptibility to infections. Our study revealed that, compared to conventional therapy, patients who received a combination therapy with belimumab experienced a lower incidence of TAEAs. This reduction may be attributed to a more rapid tapering of steroids and immunosuppressants. Moreover, the infections reported were predominantly mild in nature, and no patient discontinued belimumab treatment due to these events. Liu et al. (2022) suggested that belimumab use in dialysis patients is safe, reporting only one case of pulmonary infection among seven dialysis patients in their study. In our study, one out of four dialysis patients experienced gastrointestinal infection in our cohort. Therefore, larger-scale studies involving dialysis patients are warranted to comprehensively evaluate the safety profile of belimumab use in this population.

Our study has several limitations that need to be acknowledged. These include the relatively short follow-up duration, the single-center design, the small sample size. Additionally, in our cohort, some patients were clinically diagnosed with LN and lacked renal pathological data, which means the diagnosis of LN could not be fully confirmed and the belimumab group notably lacked cases of Classes II, III, and VI lupus nephritis. Therefore, our data may have a certain degree of selection bias and may not represent all patients with LN. However, given the recent approval of belimumab for treating SLE in China, our study contributes valuable objective data to the research on the safety and efficacy of belimumab specifically in Chinese patients with LN. To address these limitations and provide more robust evidence, future studies should aim for a multi-center design with a larger sample size and a longer follow-up duration. This would allow for a more comprehensive evaluation of the therapeutic effects and potential adverse events associated with belimumab therapy in this particular population.

Our study provides compelling evidence supporting the beneficial effects of belimumab on renal performance improvement, disease activity reduction, glucocorticoid dose reduction, and the diminution of TEAEs in Chinese patients with LN. Nevertheless, further controlled, large-scale, randomized clinical trials are warranted to confirm and validate these findings. Conducting such trials would enhance the strength of evidence regarding the efficacy and safety of belimumab as a therapeutic option for LN patients, ultimately guiding clinical practice and improving patient outcomes.

Supplemental Information

Supplemental information 1, supplemental information 2, supplemental information 3, funding statement.

This work was supported by National Natural Science Foundation of China (No. 82300803), Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare (2022QNRCYX-XYF), and the Outstanding Young Talents Program of the First Affiliated Hospital of Fujian Medical University (YJCQN-A-XYF2021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Additional Information and Declarations

The authors declare there are no competing interests.

Zishan Lin conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Bingjing Jiang performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Wenfeng Wang analyzed the data, prepared figures and/or tables, and approved the final draft.

Caiming Chen analyzed the data, prepared figures and/or tables, and approved the final draft.

Yujia Wang analyzed the data, prepared figures and/or tables, and approved the final draft.

Jianxin Wan analyzed the data, prepared figures and/or tables, and approved the final draft.

Yanfang Xu conceived and designed the experiments, authored or reviewed drafts of the article, and approved the final draft.

The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):

This study was performed in accordance with the Helsinki Declaration and approved by the ethics committee of the First Affiliated Hospital of Fujian Medical University [2015]084-2. Written informed consent was obtained from each patient, and data are available upon request.

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Rituximab: the Lupus Journey

• Lupus (S Manzi, Section Editor)
• Published: 06 January 2015
• Volume 1 , pages 30–41, ( 2015 )

Cite this article

• Lucía Ramos MD 1 &
• David Isenberg MD FRCP 2  

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Opinion statement

Since the 1950s, lupus has changed from being a life-threatening condition to being treatable in most cases thanks to the introduction of steroids, immunosuppressive drugs, dialysis and renal transplantation. However, apart from the introduction of mycophenolate mofetil, successful new drugs for lupus have been hard to find in the past two decades. In an assessment of our lupus nephritis cohort over the past 30 years (Croca et al. , Rheumatology. 11; 50:1424-1430), we reported that both morbidity and mortality have changed little during this period, suggesting that we have optimized the use of corticosteroids and conventional immunosuppressive drugs. If we want to seek further improvement in outcome, new approaches will be necessary. In this review, we will focus on the use of rituximab in the treatment of systemic lupus erythematosus (SLE). Although not fully understood, it has become clear that B cells play a key role in SLE pathogenesis. They are implicated in the production of autoantibodies, presentation of autoantigen to T cells, T cell activation and cytokine production. In theory, B cell-targeted therapies which eliminate pathogenic B cells and promote the expansion and function of protective B cells, or both, should be beneficial (Rahman and Isenberg, N Engl J Med. 2008 ; 358:929–39), (Yildirim-Toruner and Diamond, J Allergy Clin Immunol. 2011 ; 127:303-12). Many open-label and registry studies do indeed report the successful use of rituximab in both renal and non-renal lupus. However, two major clinical trials using it failed to meet their end points. We review the road travelled by rituximab as a lupus treatment in the past 14 years and consider where the journey is heading.

Key Messages

• Rituximab is a safe and effective treatment for refractory SLE patients.

• Early treatment with Rituximab seems to be effective and can reduce steroid burden.

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Introduction

Rituximab is a chimeric mouse/human monoclonal antibody against the B cell-specific antigen CD20, which depletes B cells from peripheral blood. Initially, it was approved in 1997, for the treatment of relapsed or refractory non-Hodgkin’s lymphoma [ 2 , 3 ]. Most observers in the 1990s seemed to believe that rheumatoid arthritis (RA) was principally caused by abnormalities of T cell function and cytokine excess. In contrast, Professor Jo Edwards and Dr. Geraldine Cambridge, based at the University College London, did not. They became convinced that the role of the B lymphocyte in rheumatoid arthritis was not fully appreciated, and, based on this belief, they took the view that anything that could dampen down B cell activity would be a useful therapeutic approach. Professor Edwards tried to get access to this drug to use in rheumatoid arthritis from Roche, who manufactures it, on several occasions. It was not until the fourth time of asking that the company gave him a sufficient quantity, initially to treat five patients, all of whom responded very well with ACR50 or 70 responses. These first rheumatoid arthritis patients were treated in 1999.

Supporting the same theory, one of us (DAI) felt that if rituximab was going to work for rheumatoid arthritis, where the data that B cells were a major pathogenetic factor was less compelling than with lupus, clearly this drug ought to be given to patients with systemic lupus erythematosus (SLE). After a face-to-face interview with the Use of Medicines Committee at University College Hospital (UCH), he was granted permission, in 2000, to treat patients with lupus who had failed conventional immunosuppressive therapy. This was the first open, uncontrolled study of rituximab for patients with SLE. Thus began an odyssey that this review reflects, highlighting both the high points of the journey and its bleaker moments.

Open-Label Studies

The off-label use of rituximab was first reported in 2002, at UCH by Leandro et al. [ 4 ], and since then, it has been increasingly used in patients with SLE. Following this initial attempt, many open-label studies have been published trying to show the efficacy of rituximab in the treatment of patients with SLE with active, renal or non-renal, disease poorly controlled despite standard immunosuppressive treatment used for sufficient time at optimal doses [ 5 – 10 ].

Casals et al. [ 11 ] reviewed the evidence of the therapeutic use of rituximab in 188 adults with active, multi-organ SLE (with three or more clinical features) refractory to corticosteroid and immunosuppressive drugs. They reported a clinical response in 171 (91 %) of the patients treated with rituximab. Two rituximab regimens that were always administrated with steroids to minimize allergic responses [ 27 ] were used. One regime that is recommended for the treatment of lymphoma prescribes 375 mg/m 2 of rituximab weekly for 4 weeks and the other uses two 1000-mg doses separated by 15 days. They reported a higher rate of therapeutic response in patients treated with four weekly doses (94 vs 83 %, p  = 0.048). This finding suggests that some cases may require higher doses of rituximab to achieve a clinical response for induction therapy.

Given that renal disease occurs in 30–60 % of all patients with SLE at some time during the disease, major efforts have been made to prove the efficacy of rituximab in the last decade [ 9 ]. Casals et al. [ 11 ] also analyzed lupus nephritis (LN) patients in their systematic review. They described 106 biopsy-proven LN patients who had been treated with rituximab. In 52 (49 %) cases, rituximab was administered for LN refractory to standard therapies, in 37 (35 %) for LN flare and in 17 (16 %) as first-line therapy. A favourable therapeutic response (partial or complete response; for definitions, see Table  1 ) was achieved in 73 (69 %) patients, 8 (80 %) in type III LN patients, 26 (67 %) in type IV, 4 (57 %) in type V and 18 (78 %) in mixed membranous-proliferative LN. In conclusion, they found a global efficacy of 70 %, with half the patients each having a complete and partial response.

The LESIMAB study, a multicentre longitudinal study, has provided new data showing that rituximab can result in a high response rate in patients with refractory SLE after 10 weeks following its infusion [ 12 ]. One hundred twenty eight patients with refractory lupus were treated with at least one infusion of rituximab, 63 of them had lupus nephritis (55 patients with kidney biopsy). Seventy eight percent of the patients achieved a response rate at the end of the study (see Table  1 ) with a mean time of 3 to 4 months, accompanied by a notable decrease in steroid requirement. The patients were relapse free for a mean of 10.8 months. Only 38 % of responders experienced a flare (mostly mild) after the final rituximab infusion. They did not compare directly both doses of infusion, but they found that the regimen of four doses of rituximab was associated with a fivefold elevated risk of serious infection compared to two doses.

Gregersen and Jayne discussed the evidence derived from clinical trials and case studies in the period between 2004 and 2012 in a systematic review (in total, 300 patients were included in 21 studies with a follow-up period ranged from 3 months to over 36 months) [ 13 ]. They confirmed that the most frequent indication for rituximab therapy was refractory or relapsing lupus nephritis, the time to remission being longer than 6 months, with partial remission in less than 6 months; proliferative lupus nephritis was the most common histological diagnosis (75 %). They also observed that patients with class III lupus nephritis had greater improvement with rituximab than patients with class IV or V lupus nephritis. As other investigators have observed, they found that, as expected, rituximab seemed to have decreased efficacy in individuals with renal failure. Thus, eGFR <60 ml/min/1.73 m 2 and nephrotic syndrome were features predictive of a poor prognosis in patients [ 14 , 15 ]. Patients with nephrotic syndrome may excrete rituximab more rapidly, along with albumin and immunoglobulins. If this possibility is a concern, it might be appropriate to give more frequent doses of rituximab [ 16 , 17 ].

Another long-term follow-up study of 25 LN patients, treated with a combination of rituximab, cyclosporine and glucocorticoids [ 7 ], showed that renal response following treatment mainly occurred after a median time of 12 months in 22 patients, 16 of them achieved complete response after 2 years of follow-up, proving a significant improvement in renal biopsies as well. Furthermore, only six renal flares were observed in those patients, a low rate, taking into account that the patients included had relapsing disease at inclusion. The fact that they observed a transition from partial to complete response during the second year of follow-up indicates that clinical trials in LN need longer follow-up.

Finally, an open-labelled clinical study of 18 lupus nephritis patients suggested that the combination of rituximab and low-dose intravenous cyclophosphamide can be an effective and well-tolerated therapeutic option for refractory LN with an overall response rate of 72 % at 6 months [ 9 , 18 ].

Registry Data

Several registries have been established trying to reflect the use of rituximab in actual clinical practice. The UK-BIOGEAS Registry pooled data from European cohorts of 164 patients with biopsy-proven lupus nephritis refractory patients [ 19 ]. In 82 (50 %) cases, rituximab was administered for LN refractory to standard therapies, in 69 (42 %) for LN flare and in 13 (8 %) as first-line therapy. The renal biopsy data showed type IV LN in 93 (57 %) patients, type III in 26 (16 %), type V in 20 (12 %), type II in 6 (4 %) and mixed-membranous LN with proliferative lesions in 19 (12 %). Response rates were assessed at 6 months in 110 patients. They found a favourable clinical response in 67 % of patients at both 6 and 12 months with a rate of complete response of 27 % at 6 months and 30 % at 12 months (see Table  1 ). The remaining 42 (33 %) were classified as non-responders. Furthermore, a different rate of response was found in accordance with the ISN/RPS histopathological classification, with a fourfold higher rate of CR at 12 months in patients with proliferative-membranous LN (70 %) in comparison with those with type IV LN (22 %).

The French AutoImmunity and Rituximab Registry (AIR) analyzed the efficacy of rituximab treatment in 136 lupus patients [ 20 ]. One hundred thirteen patients with at least 3 months follow-up visit (not sure what this means, at least one 3-month follow-up?) were assessed. An overall response was observed in 87 (77 %) and a corticosteroid-sparing effect noted. The response to rituximab overall did not differ significantly between patients receiving rituximab monotherapy and those given concomitant immunosuppressive agents, but tended to be higher in those receiving rituximab monotherapy (84 vs 70 %, p  = 0.08). Thirty one of the 36 responders who were followed up for more than 6 months (41 %) experienced a relapse 14.9 ± 7.6 months after the last rituximab infusion. Although the relapse rate was similar, relapses occurred earlier in patients not taking immunosuppressive agents than in those taking them. Twenty five of the 31 relapsed patients received retreatment with rituximab. After retreatment, a response was noted in 20 of 22 (91 %) patients (no available data from the other three patients). Four patients received regular retreatment with rituximab as maintenance therapy every 6 months, and two others after a first relapse episode. These patients did not relapse during maintenance therapy after a mean follow-up of 22 months.

The German Registry of Autoimmune Diseases (GRAID) [ 21 ] analyzed 85 lupus patients in whom rituximab was used because of inefficacy with conventional treatment in 71 (89.9 %), side effects in 25 (31.6 %) and/or contraindications in 11 (13.9 %) patients. They observed a complete treatment response in 37 (46.8 %) of patients, a partial response in 27 (34.2 %) (see Table  1 ) and 15 (19 %) patients did not respond.

Clinical Trials

In spite of these encouraging data, rituximab failed to meet its primary or secondary end points in two randomized controlled trials comparing the addition to rituximab or placebo to standard of care in extra-renal lupus (EXPLORER) [ 22 ] and in lupus nephritis (LUNAR) [ 23 •]. There are a number of possible explanations for these results, including differences in the types of patients recruited in terms of disease activity, background immunosuppressives, use of active comparator drug, rituximab dosing regimen, very high doses of concomitant steroids, steroid tapering, adverse events, follow-up period, non-powered sample size and inability of disease activity instruments to capture response. Conversely, it is true that responses in open-label studies may be difficult to interpret due to variable doses and use of concomitant drugs, observer bias, uncontrolled use of steroids and other treatments and regression to the mean for patients recruited during severe flares [ 24 ••, 25 – 27 ].

However, post hoc LUNAR trial analysis, as well as other systematic reviews, has supported the view that rituximab is effective in inducing partial and, to a lesser extent, complete remission of lupus nephritis [ 16 , 28 ].

In a post hoc analysis, the LUNAR trial showed a trend toward the benefit in African-American and Hispanic patients with lupus nephritis [ 29 ]. Few studies report data on ethnicity in lupus patients treated with rituximab. However, in some, black ethnicity has been associated with failure to achieve B cell depletion and, consequently, with the absence of remission or non-response [ 13 , 30 – 32 ].

Efforts have been made to find biologic response markers of use in patients given rituximab [ 33 ]. The aim in depleting B cell lymphocytes is to diminish their differentiation into plasma cells and, therefore, decrease the production of autoantibodies. Specific B cell depletion therapy with rituximab improves peripheral B cell abnormalities in SLE patients and it is associated with a reduction in anti-dsDNA, anticardiolipin and antinucleosome antibody levels, but no change is seen in anti-Ro, anti-La, anti-Sm or anti-RNP antibodies [ 34 ]. These findings indicate that anti-ENA antibodies are secreted by long-lived plasma cells, whereas anti-DNA/nucleosome/anticardiolipin antibodies are coming, at least in a proportion of patients, from short-lived plasma cells.

Vital et al. [ 24 ••] studied the effects on B cell depletion in detail. B cells were shown to predict patterns of response and relapse. They measured the peripheral blood B cells in 39 rituximab-treated SLE patients. To do this, they used a highly sensitive flow cytometry (HSFC) technique which can enumerate B cells at levels 50–100 times lower than conventional techniques. They reported that an incomplete B cell depletion at 6 weeks was associated with lower clinical response rates at 26 weeks. All patients with complete B cell depletion had major or partial clinical response, and those who did not respond had persistent B cells after the second infusion of rituximab. The reduction in levels of B cells in peripheral blood occurs within days to weeks and the effect is sustained for up to 6 months on average, although earlier depletion is relatively common and rarely it can be much longer. We have a patient treated with rituximab (1 g twice) in 2001 who remains B cell depleted 13 years later (unpublished observation). Complete deletion of circulating B cells increases the likelihood of a clinical response. Inevitably, relapses do not become apparent until repopulation of memory B cells and plasmablasts occurs. Indeed, the timing of relapses can be predicted with reasonable accuracy by the levels of the cells at repopulation. Even in the EXPLORER and LUNAR trials, B cell-depleting therapy was associated with statistically significant improvement in the serological markers of disease activity, namely a reduction in the anti-dsDNA antibody levels and an increase in C3 levels.

Broadly speaking, the degree of B cell depletion accords with the overall response to rituximab treatment. Thus, the effectiveness of the B cell depletion correlates with better clinical outcome. Failure to achieve adequate depletion is often linked to poor clinical outcome. However, the correlation is not absolute since complete B cell depletion may not bring about clinical remission and an incomplete depletion may still lead to some clinical improvement. As Lazarus et al. [ 35 ] demonstrated, patients with SLE respond differently to B cell depletion therapy depending on the duration of B cell depletion and their levels of anti-dsDNA antibodies. They analyzed 61 refractory SLE patients treated with rituximab. They observed that SLE patients respond differently to B cell depletion depending on its duration, the levels of anti-dsDNA antibodies and the type of B cells that repopulate. They found patients with very low B cell numbers who relapsed with high anti-dsDNA antibody levels, whereas some patients with low anti-dsDNA antibody levels relapsed with similar numbers of B cells found prior to rituximab treatment. In those patients with high anti-dsDNA levels, they tried to identify the B cell subset most likely to be implicated. They found that plasmablasts are the type that dominates the repopulating B cells.

Finally, Carter et al. [ 36 •] determined whether serum B cell activating factor (BAFF) levels correlate with relapse or remission in SLE patients following treatment with rituximab. They monitored the serum BAFF levels of 35 patients for a minimum of 18 months. Ten patients remained in remission for the whole period but 25 experienced a relapse, 22 of them were treated with another course of rituximab. They found that BAFF levels are inversely related to B cell numbers after treatment with rituximab, with peak levels correlating to the nadir B cell numbers. Flare at the lowest B cell counts was associated with the highest serum BAFF levels. High BAFF levels after B cell depletion and repopulation of peripheral B cells distinguished those patients with relapsing disease from those remaining in remission. Furthermore, a low BAFF ‘state’ posttreatment appeared to indicate a favourable clinical outcome.

They observed that serum BAFF levels during relapse after B cell depletion were significantly elevated in comparison with those during the disease flare prior to treatment. Serum BAFF levels have been shown to correlate positively with levels of anti-dsDNA antibodies, a correlation that seems to be preserved posttreatment. The observations imply a significant role for BAFF in encouraging disease flare after B cell depletion. Sequential depletion may encourage ever increasing BAFF levels (and rising dsDNA antibody levels) with disease flare occurring even at low B cell numbers. It is tempting to speculate that the use of belimumab (which is an anti-BAFF biologic) may be of value in these patients [ 37 •, 38 ].

In terms of side effects, rituximab used in combination with immunosuppressive therapies has raised concerns about increased risks of infection. However, rituximab therapy is well tolerated and has a low rate of side effects. The most frequent adverse effects reported in literature were infections (predominantly mild respiratory and urinary infections due to common microorganisms), infusion reactions (related to the lack of premedication) and hematologic abnormalities (mainly, neutropenia) [ 13 , 15 ]. Very few cases (<10) of progressive multifocal leukoencephalopathy (PML) have been reported in individuals with SLE being treated with rituximab in combination with other immunosuppressive drugs. However, its attribution exclusively to rituximab is not warranted, as more cases (around 20–30) have been reported in patients with longstanding active SLE (which itself can increase the risk of PML) not given this biologic, who were treated with various standard immunosuppressive treatments as well as corticosteroids [ 39 , 40 ].

New Approaches

In the last few years, the idea of treating newly diagnosed SLE patients with rituximab has been introduced, partly to help reduce chronic steroid usage. Ezeonyeji and Isenberg [ 41 ] described a steroid-sparing regimen in eight newly diagnosed, mainly non-renal, SLE patients given rituximab at diagnosis. They found that rituximab was as effective as the conventional treatment given to controls (three, matched for each rituximab treated patient). This approach also reduced the cumulative steroid burden.

Recently, Condon et al. [ 42 ••] reported a larger prospective observational single-centre cohort study, in which a rituximab-based therapy, without oral steroids (the rituxilup protocol), was used in 50 biopsy-proven active class III, IV or V lupus nephritis patients. At a median time of 37 weeks, 45 (90 %) of the patients had achieved partial or complete response (see Table  1 ). The time to complete or partial response was not influenced by class of LN at baseline. There were 12 relapses in 11 patients (22 %), all nephrotic with a median time to relapse from remission of 65.1 weeks. Of these, eight and four occurred in patients with complete and partial response, respectively. Seven relapses (in six patients) were treated with rituximab, obtaining a complete response is three, a partial response in one and three non-responders. Only two patients required maintenance steroids because of severe systemic symptoms. In this study, 24 (48 %) patients had negative anti-dsDNA antibodies and 22 (44 %) patients had pure class V lesions at baseline, 18 % of them achieving a complete response at 6 months rising to 36 % by 1 year. This study showed high rates of renal remission, without reduction in efficacy or increase in relapse rates, at least after 3 years of follow-up, and very few required oral steroids [ 42 ••, 43 , 44 ].

Conclusions

The use of rituximab to treat SLE now goes back 14 years. Our unit at the University College London has made a major contribution to these studies (see Table  2 ). It seems clear that most physicians who have used it agree that, while it is not a cure for SLE, rituximab can be most effective for virtually all aspects of the disease. The two clinical trials (EXPLORER and LUNAR), which failed, seem likely to have done so because of trial design issues. Although the recent reports of the use of rituximab at the time of diagnosis are most encouraging, full acceptance of the effectiveness of rituximab awaits a successful clinical trial (Table  3 ). The RITUXILUP study, which aims to compare the use of rituximab plus mycophenolate mofetil to steroids plus mycophenolate mofetil in biopsy-proven newly diagnosed renal lupus, may be the necessary catalyst to the widespread acceptance of rituximab in the treatment of patients with SLE.

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Lucía Ramos declares that he has no conflict of interest.

David Isenberg was a previous consultant for GlaxoSmithKline outside of the submitted work.

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Ramos, L., Isenberg, D. Rituximab: the Lupus Journey. Curr Treat Options in Rheum 1 , 30–41 (2015). https://doi.org/10.1007/s40674-014-0003-2

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Kezar Study Evaluates Potential New Treatment for People with Lupus Nephritis

Study title:.

A Phase 2b, Randomized, Controlled Double-blind, Multicenter Study Comparing the Efficacy and Safety of Zetomipzomib (KZR-616) 30 mg or 60 mg With Placebo in Patients With Active Lupus Nephritis 

Sponsor Name:

Kezar Life Sciences

Purpose of Study:

The PALIZADE clinical study is evaluating zetomipzomib for the treatment of lupus nephritis, its side effects, and how it affects proteins in the urine.

What Does This Study Involve?

• A screening visit is conducted by a study coordinator or clinical research nurse to determine if you are eligible to participate in the clinical trial. This includes the informed consent process, medical history and physical examination, vital signs and measurements, laboratory tests, and any necessary additional assessments such as X-rays.
• The study treatment will last for 52 weeks (1 year) with site visits occurring about every 4 weeks. At these visits, a study coordinator, clinical research nurse, or physician will conduct assessments to determine your response to therapy.
• Following 4 weeks after completion of the treatment, there will be 1 follow-up visit to report any side effects or other safety information to the investigator.
• There is a 2 in 3 chance of being placed in a patient group receiving zetomipzomib. All patients will be randomized into one of three groups to receive either a 30 mg dose of zetomipzomib, a 60 mg dose of zetomipzomib, or placebo through a weekly injection under the skin. During the clinical trial, you will be able to continue taking other medications that your physician has prescribed for treating your lupus nephritis.

Accommodations for study participation, including clinical trial assessments at no cost, remote home trial services*, and travel concierge* may be available. 

*Remote home trial and travel concierge services vary by clinical trial location.

To Consider Participation in This Study, You Must:

• Be at least 18 years of age.
• Have a kidney biopsy completed within the last year showing a clinical diagnosis of active lupus nephritis (Class III or IV, with or without Class V, or Class V alone). If you have not had a biopsy in the past year, you will need to complete a biopsy during the screening period for participation in the clinical trial.
• Have a urine protein to creatinine ratio (UPCR) ≥1.0 (Class III/IV +/-V) or UPCR ≥2.0 (Class V)
• Have a body mass index (BMI) of ≥18 kg/m2.
• Have a positive ANA test result and/or a positive anti-dsDNA serum antibody test. 
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• Positive test at Screening for HIV, hepatitis B/C.
• Known intolerance to mycophenolate mofetil or equivalent and corticosteroids.

Study Type:

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• Review Article
• Published: 19 March 2020

Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy

• Naomi I. Maria   ORCID: orcid.org/0000-0002-3452-2515 1 &
• Anne Davidson 1  

Nature Reviews Rheumatology volume  16 ,  pages 255–267 ( 2020 ) Cite this article

9435 Accesses

72 Citations

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• Lupus nephritis
• Medical research
• Systemic lupus erythematosus

Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Although the prognosis of LN has improved substantially over the past 50 years, outcomes have plateaued in the USA in the past 20 years as immunosuppressive therapies have failed to reverse disease in more than half of treated patients. This failure might reflect disease complexity and heterogeneity, as well as social and economic barriers to health-care access that can delay intervention until after damage has already occurred. LN progression is still poorly understood and involves multiple cell types and both immune and non-immune mechanisms. Single-cell analysis of intrinsic renal cells and infiltrating cells from patients with LN is a new approach that will help to define the pathways of renal injury at a cellular level. Although many new immune-modulating therapies are being tested in the clinic, the development of therapies to improve regeneration of the injured kidney and to prevent fibrosis requires a better understanding of the mechanisms of LN progression. This mechanistic understanding, together with the development of clinical measures to evaluate risk and detect early disease and better access to expert health-care providers, should improve outcomes for patients with LN.

Lupus nephritis (LN) is a heterogeneous complication of systemic lupus erythematosus that remains a considerable unmet medical need.

Genetic and epigenetic factors confer risks of LN incidence and progression.

Single-cell analyses and enhanced microscopic analyses of renal tissues are yielding new information about LN pathogenesis and the progression of chronic kidney disease.

Improvements in risk assessment using genetic or transcriptomic biomarkers could enable the design of clinical trials to prevent LN onset and progression.

Trials might need to be tailored according to the genetic profile of the patient, a biomarker-based evaluation of their renal tissue and/or the mechanism of action of each new drug.

Developments in the understanding of tubulointerstitial injury and repair are yielding new strategies for preserving renal function and preventing fibrosis.

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Acknowledgements

The work of the authors was funded by The Lupus Research Alliance, the US National Institutes of Health (grant RO1 AR064811–01 to A.D.) and the US Department of Defense (grant W81XWH-17–1–0657 to A.D.).

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References were selected using Medline search and the terms ‘lupus’ and/or ‘nephritis’ with ‘therapies’, ‘inflammation’, ‘endothelial cells’, ‘podocytes’, ‘biomarkers’, ‘macrophages’, ‘dendritic cells’, ‘T cells’, ‘B cells’, ‘cytokines’, ‘fibrosis’ and ‘renal tubules’. Articles published between 2016 and 2019 were given preference for inclusion. In addition, a personal collection of articles was used that includes ~5,000 references related to SLE and novel therapies.

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A loss of capillary structure leading to reduced density of microvascular networks.

A response to severe injury in which crescent-shaped glomerular lesions that consist of epithelial cells, fibroblasts, immune cells and matrix form adjacent to the Bowman’s capsule.

A podocyte reaction to injury or damage in which the epithelial foot processes become flattened and lose their barrier function, resulting in proteinuria.

A network of small blood vessels and supporting cells that forms the initial structural component of the nephron.

Scarring of the glomeruli that leads to loss of function.

A technique used in developmental biology to study the embryonic origin of adult cells, tissues and structures.

A cell state or phenotype with progressive loss of effector cytokine or cytotoxic function owing to prolonged antigen stimulation, often characterized by the increased expression of immune checkpoint inhibitory receptors, alterations in metabolic function and a distinct transcriptional profile that differs from that of anergic cells.

The use of multiple medications to treat complex medical conditions.

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Maria, N.I., Davidson, A. Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy. Nat Rev Rheumatol 16 , 255–267 (2020). https://doi.org/10.1038/s41584-020-0401-9

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Issue Date : May 2020

DOI : https://doi.org/10.1038/s41584-020-0401-9

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Roche Holding AG

Ch0012032048, pharmaceuticals.

• Positive Phase III Results for Genentech’s Gazyva Show Superiority to Standard Therapy Alone in People With Lupus Nephritis

– The REGENCY study met its primary endpoint, demonstrating statistically significant and clinically meaningful treatment benefits in people with active lupus nephritis – – Gazyva is designed to target an underlying cause of lupus nephritis, aiming to prevent or delay progression to end-stage kidney disease – – Lupus nephritis is a potentially life-threatening manifestation of an autoimmune disease affecting 1.7 million people worldwide, primarily women; up to one-third of people on current treatments will progress to end-stage kidney disease within 10 years –

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today positive topline results from the Phase III REGENCY study of Gazyva® (obinutuzumab) in people with active lupus nephritis. In the study, a higher proportion of people treated with Gazyva plus standard therapy (mycophenolate mofetil and glucocorticoids) achieved a complete renal response (CRR) at 76 weeks compared to those treated with standard therapy alone. Safety was in line with the well-characterized profile of Gazyva. No new safety signals were identified.

“Gazyva achieved a robust complete renal response rate in lupus nephritis, which is associated with long-term preservation of kidney function and delay or prevention of end-stage kidney disease,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “Since dialysis or transplants are often required for patients with advanced kidney disease, these findings could represent an important step forward for people living with this devastating disease.”

“I am very excited about today’s announcement that the Phase III REGENCY study has met its primary endpoint,” said Dr. Brad H. Rovin, Director of Nephrology and Medical Director of the Center for Clinical Research Management at The Ohio State University Wexner Medical Center, and investigator for the REGENCY study. “The results of REGENCY are compelling. Obinutuzumab could offer the lupus community an effective new treatment option for controlling this difficult disease that can be associated with high morbidity for individuals living with lupus.”

Two key secondary endpoints showed statistically significant and clinically meaningful benefits with Gazyva – the endpoint proportion of patients achieving CRR with a successful reduction of corticosteroid use, and an improvement in proteinuric response (both at 76 weeks). These endpoints are important indicators for achieving better disease control in lupus nephritis. Other secondary endpoints were not statistically significant, but numerically greater responses were observed for Gazyva in several endpoints.*

Data are being shared with health authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, with the goal of making this potential new treatment option for lupus nephritis available as soon as possible. Data are also being submitted for publication in a medical journal and presentation at a future medical congress.

Lupus nephritis is a potentially life-threatening manifestation of an autoimmune disease that affects approximately 1.7 million people worldwide, predominantly women and mostly women of color and childbearing age. In lupus nephritis, disease-causing B cells drive persistent inflammation that damages the kidneys. Despite current treatment options, up to a third of people will develop end-stage kidney disease within 10 years, where dialysis or transplant are the only available options and the risk of mortality is high. Data suggest that Gazyva depletes disease-causing B cells, helping to limit further damage to the kidneys and potentially preventing or delaying progression to end-stage kidney disease.

Gazyva was granted Breakthrough Therapy Designation by the FDA in 2019, based on data from the Phase II NOBILITY study. Breakthrough Therapy Designation is designed to accelerate the development and regulatory review of medicines intended to treat serious or life-threatening conditions where preliminary clinical evidence has indicated they may demonstrate substantial improvement over existing therapies.

In addition to REGENCY, Gazyva is being investigated in children and adolescents with lupus nephritis, people with membranous nephropathy, childhood-onset idiopathic nephrotic syndrome and systemic lupus erythematosus (SLE), an autoimmune disease that commonly affects the kidneys and can lead to lupus nephritis. Our pipeline also includes RG6299 (ASO factor B), an antisense oligonucleotide therapy being investigated in people with primary immunoglobulin A nephropathy at high risk of progression, Lunsumio® (mosunetuzumab), a first-in-class CD20xCD3 T-cell engaging bispecific antibody being investigated in SLE, PiaSky® (crovalimab), a novel recycling monoclonal antibody being investigated in atypical hemolytic uremic syndrome and RG6382, a CD19xCD3 T-cell engaging bispecific antibody being investigated in SLE.

*Mean change in estimated glomerular filtration rate at 76 weeks, death or renal-related events through week 76, and overall renal response at 50 weeks.

About Gazyva in Kidney Diseases

Gazyva® (obinutuzumab) is a Type II engineered humanized monoclonal antibody designed to attach to CD20, a protein found on certain types of B cells. In lupus nephritis, disease-causing B cells drive persistent inflammation that damages the kidneys. We can target an underlying cause of lupus nephritis to help gain better control of the disease by depleting disease-causing B cells with Gazyva, aiming to protect the kidneys from further damage and potentially prevent or delay progression to end-stage kidney disease.

Gazyva is already approved in 100 countries for various types of lymphoma. In the United States, Gazyva is part of a collaboration between Genentech and Biogen.

About the REGENCY Study

REGENCY [ NCT04221477 ] is a Phase III, randomized, double-blind, placebo-controlled, multicenter study investigating the efficacy and safety of Gazyva® (obinutuzumab) plus standard therapy (mycophenolate mofetil and glucocorticoids) in people with active/chronic International Society of Nephrology/Renal Pathology Society 2003 proliferative Class III or IV lupus nephritis, with or without Class V. The study enrolled 271 people, who were randomized 1:1 to receive either biannual intravenous dosing of Gazyva plus standard therapy or placebo plus standard therapy. REGENCY was designed based on robust Phase II data and conducted during the COVID-19 pandemic. The study population was representative of the real-world population of people with lupus nephritis. The primary endpoint was the proportion of people who achieved complete renal response (CRR) at 76 weeks. Key secondary endpoints included the proportion of people who achieved CRR at week 76 with successful reduction of corticosteroid use (prednisone taper); the proportion who achieved proteinuric response at 76 weeks; mean change in estimated glomerular filtration rate at 76 weeks; death or renal related events through week 76 and overall renal response at 50 weeks. Safety and tolerability were also assessed.

About Lupus Nephritis

Lupus nephritis is a potentially life-threatening manifestation of systemic lupus erythematosus, an autoimmune disease that commonly affects the kidneys. Lupus nephritis affects approximately 1.7 million people worldwide. Lupus nephritis has a profound impact on the lives and outlook of those affected and even with the latest treatments, the damage caused to the kidneys usually gets worse over time, with up to a third of people progressing to end-stage kidney disease within 10 years, where the only options are dialysis or transplant. Lupus nephritis predominantly affects women, mostly women of color and usually of childbearing age. Currently, there is no cure.

Gazyva U.S. Indications

Gazyva® (obinutuzumab) is a prescription medicine used:

• With the chemotherapy drug, chlorambucil, to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment.
• With the chemotherapy drug, bendamustine, followed by Gazyva alone for follicular lymphoma (FL) in adults who did not respond to a rituximab-containing regimen, or whose FL returned after such treatment.
• In combination with chemotherapy, followed by Gazyva alone in those who responded, to treat stage II bulky, III, or IV FL in adults who have not had previous FL treatment.

Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that can become serious or life-threatening, including:

• Hepatitis B Virus (HBV): Hepatitis B can cause liver failure and death. If the patient has a history of hepatitis B infection, Gazyva could cause it to return. Patients should not receive Gazyva if they have active hepatitis B liver disease. The patient’s doctor or healthcare team will need to screen them for hepatitis B before, and monitor the patient for hepatitis during and after, their treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Symptoms of hepatitis include: worsening of fatigue and yellow discoloration of skin or eyes.
• Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and serious brain infection caused by a virus. PML can be fatal. The patient’s weakened immune system could put them at risk. The patient’s doctor will watch for symptoms. Symptoms of PML include: confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems.

Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must tell their healthcare provider if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that may become severe or life threatening, including:

• Infusion Reactions: These side effects may occur during or within 24 hours of any Gazyva infusion. Some infusion reactions can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening infusion reactions. If the patient has a reaction, the infusion is either slowed or stopped until their symptoms are resolved. Most patients are able to complete infusions and receive medication again. However, if the infusion reaction is life-threatening, the infusion of Gazyva will be permanently stopped. The patient’s healthcare team will take steps to help lessen any side effects the patient may have to the infusion process. The patient may be given medicines to take before each Gazyva treatment. Symptoms of infusion reactions may include: fast heartbeat, tiredness, dizziness, headache, redness of the face, nausea, chills, fever, vomiting, diarrhea, rash, high blood pressure, low blood pressure, difficulty breathing, and chest discomfort.
• Hypersensitivity Reactions Including Serum Sickness: Some patients receiving Gazyva may have severe or life-threatening allergic reactions. This reaction may be severe, may happen during or after an infusion, and may affect many areas of the body. If an allergic reaction occurs, the patient’s doctor will stop the infusion and permanently discontinue Gazyva.
• Tumor Lysis Syndrome (TLS): Tumor lysis syndrome, including fatal cases, has been reported in patients receiving Gazyva. Gazyva works to break down cancer cells quickly. As cancer cells break apart, their contents are released into the blood. These contents may cause damage to organs and the heart, and may lead to kidney failure requiring the need for dialysis treatment. The patient’s doctor may prescribe medication to help prevent TLS. The patient’s doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness.
• Infections: While the patient is taking Gazyva, they may develop infections. Some of these infections may be fatal and severe, so the patient should be sure to talk to their doctor if they think they have an infection. Patients administered Gazyva in combination with chemotherapy, followed by Gazyva alone are at a high risk of infections during and after treatment. Patients with a history of recurring or chronic infections may be at an increased risk of infection. Patients with an active infection should not be treated with Gazyva. Patients taking Gazyva plus bendamustine may be at higher risk for fatal or severe infections compared to patients taking Gazyva plus CHOP or CVP.
• Low White Blood Cell Count: When the patient has an abnormally low count of infection-fighting white blood cells, it is called neutropenia. While the patient is taking Gazyva, their doctor will do blood work to check their white blood cell count. Severe and life-threatening neutropenia can develop during or after treatment with Gazyva. Some cases of neutropenia can last for more than one month. If the patient’s white blood cell count is low, their doctor may prescribe medication to help prevent infections.
• Low Platelet Count: Platelets help stop bleeding or blood loss. Gazyva may reduce the number of platelets the patient has in their blood; having low platelet count is called thrombocytopenia. This may affect the clotting process. While the patient is taking Gazyva, their doctor will do blood work to check their platelet count. Severe and life-threatening thrombocytopenia can develop during treatment with Gazyva. Fatal bleeding events have occurred in patients treated with Gazyva. If the patient’s platelet count gets too low, their treatment may be delayed or reduced.
• Disseminated Intravascular Coagulation (DIC): Fatal and severe DIC has been reported in people receiving GAZYVA. DIC is a rare and serious abnormal blood clotting condition that should be monitored and managed by your doctor as it can lead to uncontrollable bleeding

The most common side effects of Gazyva in CLL were infusion-related reactions and low white blood cell counts.

The most common side effects seen with GAZYVA in a study that included relapsed or refractory NHL, including FL patients were infusion-related reactions, fatigue, low white blood cell counts, cough, upper respiratory tract infection, and joint or muscle pain.

The most common side effects seen with GAZYVA in a study that included previously untreated FL patients were infusion-related reactions, low white blood cell count, upper respiratory tract infections, cough, constipation and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

• Immunizations: Before receiving Gazyva therapy, the patient should tell their healthcare provider if they have recently received or are scheduled to receive a vaccine. Patients who are treated with Gazyva should not receive live vaccines.
• Pregnancy: The patient should tell their doctor if they are pregnant, think that they might be pregnant, or plan to become pregnant. Gazyva may harm their unborn baby. The patient should speak to their doctor about using Gazyva while they are pregnant. The patient should talk to their doctor or their child’s doctor about the safety and timing of live virus vaccinations to their infant if they received Gazyva during pregnancy. Patients of childbearing potential should use effective contraception while taking Gazyva and for 6 months after your Gazyva treatment.
• Breastfeeding: Because of the potential risk of serious side reactions in breastfed children, patient should not breastfeed while taking Gazyva and for 6 months after your last dose.

Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please visit http://www.Gazyva.com for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Lunsumio ® (mosunetuzumab-axgb)

Lunsumio® is a first-in-class CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. A robust clinical development program for Lunsumio is ongoing, investigating the molecule as a monotherapy and in combination with other medicines, for the treatment of people with B-cell non-Hodgkin’s lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, and other blood cancers.

Lunsumio U.S. Indication

Lunsumio® (mosunetuzumab-axgb) is a prescription medicine used to treat adults with follicular lymphoma whose cancer has come back or did not respond to previous treatment, and who have already received two or more treatments for their cancer.

It is not known if Lunsumio is safe and effective in children.

The conditional approval of Lunsumio is based on response rate. There are ongoing studies to establish how well the drug works.

What is the most important information I should know about Lunsumio?

Lunsumio may cause Cytokine Release Syndrome (CRS), a serious side effect that is common during treatment with Lunsumio and can also be severe or life-threatening.

Get medical help right away if you develop any signs or symptoms of CRS at any time, including:

• fever of 100.4°F (38°C) or higher
• low blood pressure
• fast or irregular heartbeat
• tiredness or weakness
• difficulty breathing
• feeling anxious
• dizziness or light-headedness

Due to the risk of CRS, you will receive Lunsumio on a “step-up dosing schedule.”

• The step-up dosing schedule is when you receive smaller “step-up” doses of Lunsumio on Day 1 and Day 8 of your first cycle of treatment
• You will receive a higher dose of Lunsumio on Day 15 of your first cycle of treatment
• If your dose of Lunsumio is delayed for any reason, you may need to repeat the step-up dosing schedule
• Before each dose in Cycle 1 and Cycle 2, you will receive medicines to help reduce your risk of CRS

Your healthcare provider will check you for CRS during treatment with Lunsumio and may treat you in a hospital if you develop signs and symptoms of CRS. Your healthcare provider may temporarily stop or completely stop your treatment with Lunsumio, if you have severe side effects.

What are the possible side effects of Lunsumio?

Lunsumio may cause serious side effects, including:

• numbness and tingling of the arms, legs, hands, or feet
• confusion and disorientation
• difficulty paying attention or understanding things
• forgetting things or forgetting who or where you are
• trouble speaking, reading, or writing
• sleepiness or trouble sleeping
• loss of consciousness
• muscle problems or muscle weakness
• loss of balance or trouble walking
• fever of 100.4° F (38° C) or higher
• shortness of breath
• painful rash
• sore throat
• pain during urination
• feeling weak or generally unwell
• low white blood cell counts (neutropenia). Low white blood cells can increase your risk for infection
• low red blood cell counts (anemia). Low red blood cells can cause tiredness and shortness of breath
• low platelet counts (thrombocytopenia). Low platelet counts can cause bruising or bleeding problems
• Growth in your tumor or worsening of tumor related problems (Tumor flare). Lunsumio may cause serious or severe worsening of your tumor. Tell your healthcare provider if you develop any of these signs or symptoms of tumor flare during your treatment with Lunsumio: tender or swollen lymph nodes, chest pain, cough, trouble breathing, and pain or swelling at the site of the tumor

Your healthcare provider may temporarily stop or permanently stop treatment with Lunsumio if you develop severe side effects.

The most common side effects of Lunsumio include: tiredness, rash, fever, and headache.

The most common severe abnormal lab test results with Lunsumio include: decreased phosphate, increased glucose, and increased uric acid levels.

Before receiving Lunsumio, tell your healthcare provider about all of your medical conditions, including if you:

• have ever had an infusion reaction after receiving Lunsumio
• have an infection, or have had an infection in the past which lasted a long time or keeps coming back
• have or have had Epstein-Barr Virus
• are pregnant or plan to become pregnant. Lunsumio may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Lunsumio

Females who are able to become pregnant:

• your healthcare provider should do a pregnancy test before you start treatment with Lunsumio
• you should use an effective method of birth control during your treatment and for 3 months after the last dose of Lunsumio
• are breastfeeding or plan to breastfeed. It is not known if Lunsumio passes into your breast milk. Do not breastfeed during treatment and for 3 months after the last dose of Lunsumio

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What should I avoid while receiving Lunsumio?

Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, tremors, sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of CRS or neurologic problems.

These are not all the possible side effects of Lunsumio. Talk to your healthcare provider for more information about the benefits and risks of Lunsumio.

You may report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch . You may also report side effects to Genentech at (888) 835-2555.

Please see Important Safety Information, including Serious Side Effects, as well as the Lunsumio full Prescribing Information and Medication Guide or visit https://www.Lunsumio.com .

PiaSky U.S. Indication

PiaSky® is a prescription medicine used to treat a disease called paroxysmal nocturnal hemoglobinuria (PNH) in adults and children 13 years of age or older who weigh at least 88 pounds (40 kg).

It is not known if PiaSky is safe and effective in children under 13 years of age and in people who weigh less than 88 pounds (40kg).

What is the most important information I should know about PiaSky?

PiaSky is a medicine that can affect your immune system. PiaSky may lower the ability of your immune system to fight infections

• You must complete or update your meningococcal vaccines at least 2 weeks before your first dose of PiaSky.
• If your healthcare provider decides that immediate treatment with PiaSky is needed and your meningococcal vaccination is not up to date, you should receive meningococcal vaccination as soon as possible, and receive antibiotics for as long as your healthcare provider tells you.
• If you have been given a meningococcal vaccine in the past, you might need additional vaccines before starting PiaSky. Your healthcare provider will decide if you need additional meningococcal vaccine.
• fever and a rash
• fever with a high heart rate
• fever with a headache
• headache with nausea or vomiting
• headache with a stiff neck or stiff back
• muscle aches, with flu-like symptoms
• eyes sensitive to light
• Your healthcare provider will give you a Patient Safety Card about the risk of serious meningococcal infection. Carry it with you at all times during treatment and for 11 months after your last dose of PiaSky. Your risk of meningococcal infection may continue for several months after your last dose of PiaSky. It is important to show this card to any healthcare provider who treats you. This will help them diagnose and treat you quickly.
• enroll in the PiaSky REMS program.
• counsel you about the risk of serious meningococcal infection.
• give you information about the signs and symptoms of serious meningococcal infection.
• make sure that you are vaccinated with a meningococcal vaccine and that you receive antibiotics if you need to start PiaSky right away if you are not up to date on your vaccines.
• give you a Patient Safety Card about your risk of meningococcal infection.
• muscle or bone pain
• rash or skin problems
• kidney problems
• numbness and tingling or a feeling of pins and needles especially of the hands and feet
• weakness, tiredness, or lack of energy
• stomach trouble or pain
• If you receive treatment with PiaSky, you should receive vaccines against Streptococcus pneumoniae.
• If your child receives treatment with PiaSky, your child should receive vaccines against Streptococcus pneumoniae and may receive vaccines against Haemophilus influenzae , depending on their age.
• feeling short of breath
• burning pain when passing urine

Who should not receive PiaSky?

Do not receive PiaSky if you:

• Have a serious meningococcal infection caused by Neisseria meningitidis when you are starting PiaSky treatment.
• Are allergic to crovalimab or any of the ingredients in PiaSky.

Before receiving PiaSky tell your healthcare provider about all of your medical conditions, including if you:

• have an infection or fever.
• are pregnant or plan to become pregnant. It is not known if PiaSky may harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if PiaSky passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PiaSky and other medicines can affect each other, causing side effects. Especially tell your healthcare provider if you are currently being treated with or have ever been treated with any other complementary C5 inhibitor (C5 inhibitor) medicine. PiaSky is a C5 inhibitor medicine. Know the medicines you take and the vaccines you receive. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I receive PiaSky?

• Your healthcare provider will give you your PiaSky treatment.
• Your first dose will be given through a vein by intravenous (IV) infusion on Day 1 by your healthcare provider. This is the first loading dose.
• Another loading dose will be given as an injection under the skin (subcutaneous) on Days 2, 8, 15, and 22.
• Your maintenance doses will begin on Day 29 and then will be given every 4 weeks as a subcutaneous injection.
• Your healthcare provider will prescribe the dose based on your weight. If your weight changes, tell your healthcare provider.
• Talk to your healthcare provider if you miss receiving your dose of PiaSky.
• If you are changing treatment from another C5 inhibitor such as eculizumab or ravulizumab to PiaSky, you should receive your first loading dose of PiaSky no sooner than the time you would have received your next scheduled dose of eculizumab or ravulizumab.
• a lower number of red blood cells (anemia)
• blood in your urine or dark urine
• feeling tired or low energy (fatigue)
• stomach pain
• blood clotting (thrombosis)
• difficulty swallowing
• difficulty getting or keeping an erection (erectile dysfunction)
• kidneys not working properly

What are the possible side effects of PiaSky?

PiaSky can cause serious side effects including:

• shortness of breath or trouble breathing
• pain or tightness in your chest
• feeling dizzy or lightheaded
• swelling of the throat, lips, tongue, or face
• skin itching, hives, or rash
• fever or chills
• infusion-related reactions
• respiratory tract infections including infections of the lungs, cold symptoms, and pain or swelling of the nose or throat
• viral infections
• Type III hypersensitivity reactions

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of PiaSky. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or https ://www.fda.gov/medwatch . You may also report side effects to Genentech at (888) 835-2555 .

Please see the full Prescribing Information and Medication Guide for additional Important Safety Information, including Serious Side Effects , or visit https://www.piasky.com .

About Genentech in Kidney Diseases

For 20 years, we have combined innovation, scientific expertise and commitment to patients to address unmet needs in kidney diseases. Our industry-leading pipeline includes several ongoing Phase I-III clinical studies of immune-mediated investigational therapies with the aim of bringing innovative new treatment options to people living with kidney and kidney-related diseases, including lupus nephritis, membranous nephropathy, immunoglobulin A nephropathy, atypical hemolytic uremic syndrome, childhood-onset idiopathic nephrotic syndrome and systemic lupus erythematosus, an autoimmune disease that can lead to lupus nephritis.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com .

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AURINIA ANNOUNCES JAPAN APPROVAL OF LUPKYNIS® (VOCLOSPORIN) TO TREAT LUPUS NEPHRITIS