EULAR/ERA-EDTA 2019: new developments in recommendations for the treatment of lupus nephritis

Up to 40% of patients with systemic lupus erythematosus (SLE) will develop kidney disease, which is a major cause of morbidity
.

In 2012, the European Anti-Rheumatic Alliance-European Kidney Association-European Dialysis and T Transplant Association (EULAR/ERA-EDTA) formulated a joint recommendation plan for lupus nephritis (LN), involving rheumatologists, nephrologists, and renal pathologists.

1.
Recommend 

1.
Recommend 

1.
Screening of patients with suspected LN

1.
Screening of patients with suspected LN

Patients with glomerular hematuria and/or cell type, proteinuria> 0.
5 g/24 hours (or urine protein/creatine ratio (UPCR)> 500 mg/g), and glomerular filtration rate (GFR) unexplained decrease Kidney biopsy can be done in all patients with SLE
.

Mild clinical manifestations (such as subnephrotic proteinuria) may be related to active histological lesions

Patients with glomerular hematuria and/or cell type, proteinuria> 0.

2.

APL detection

3.
Indications for immunosuppressive therapy of lupus nephritis

3.
Indications for immunosuppressive therapy of lupus nephritis

It is recommended to perform immunosuppressive therapy in active grade III or IV LN
.

For pure grade V LN, although renin-angiotensin-aldosterone system blockers are best used, the immunosuppressive recommendations for patients with proteinuria >1 g/24 hours apply to patients with proteinuria in the nephrotic range, and the prognosis is poor.

It is recommended to perform immunosuppressive therapy in active grade III or IV LN

Second, the treatment of adult LN

  The treatment goals were further determined according to the time when the treatment started
.

Post-hoc analysis from the MAINTAIN and European Lupus Nephritis Trials showed that proteinuria at 12 months is the best single predictor of long-term renal outcome (for example, the risk of end-stage renal disease (ESKD) or the doubling of serum creatine after 10 years)

  The treatment goals were further determined according to the time when the treatment started

1.

   In LN level III-IV, a review showed that mycophenolate mofetil/mycophenolate mofetil (MMF/MPA) and cyclophosphamide (CY) have similar efficacy, but there may be ethnic differences, that is, MMF may be in African descent More effective among Americans

2.

   MMF/MPA and azathioprine (AZA) are still the first choice drugs for subsequent immunosuppressive therapy, and there is sufficient therapeutic response in the initial stage

3.
Treatment of non-responsive/refractory diseases

   All first-line treatments, including MMF/MPA (2-3g/d), CY and CNI (especially TAC), as monotherapy or multi-target therapy, are recommended for the treatment of unresponsive diseases
.
B cell depletion therapy, such as RTX, although not within the above range, is also considered as a monotherapy or add-on therapy for MMF/MPA or CY; complete depletion of B cells in the circulation heralds clinical remission in several weeks
.
Recently, a successful atolizumab trial confirmed this
.
After responding to RTX, recurrence is not uncommon, but it will occur at a different time
.
Repeated doses can be considered as a method to prevent or treat recurrence
.
Although belimumab is not formally used to treat LN, informal analyses of randomized controlled trials and observational studies have shown that when added to standard care (including MMF), it may gradually reduce the risk of proteinuria and renal erythema
.
Importantly, the positive results of phase III RCT of belimumab as a supplemental therapy for LN have been announced, and the results of this study are still waiting
.
RTX and belimumab are used in combination in refractory diseases.
When there are contraindications to glucocorticoids or immunosuppressive drugs (such as infection), high-dose intravenous immunoglobulin (2g/kg) can be considered, but it is very Less need for plasma exchange
.

   All first-line treatments, including MMF/MPA (2-3g/d), CY and CNI (especially TAC), as monotherapy or multi-target therapy, are recommended for the treatment of unresponsive diseases
.
B cell depletion therapy, such as RTX, although not within the above range, is also considered as a monotherapy or add-on therapy for MMF/MPA or CY; complete depletion of B cells in the circulation heralds clinical remission in several weeks
.
Recently, a successful atolizumab trial confirmed this
.
After responding to RTX, recurrence is not uncommon, but it will occur at a different time
.
Repeated doses can be considered as a method to prevent or treat recurrence
.
Although belimumab is not formally used to treat LN, informal analyses of randomized controlled trials and observational studies have shown that when added to standard care (including MMF), it may gradually reduce the risk of proteinuria and renal erythema
.
Importantly, the positive results of phase III RCT of B cell depletion therapy such as RTX and belimumab as LN supplement therapy have been announced, and the results of this study are still waiting
.
RTX and belimumab are used in combination in refractory diseases.
When there are contraindications to glucocorticoids or immunosuppressive drugs (such as infection), high-dose intravenous immunoglobulin (2g/kg) can be considered, but it is very Less need for plasma exchange
.

4.
Adjuvant treatment for patients with lupus nephritis

4.
Adjuvant treatment for patients with lupus nephritis

    The renin-angiotensin-aldosterone system blocker (in non-pregnant patients) is recommended because it has anti-proteinuria and hypotensive effects ; it should be used with caution in patients with impaired renal function
.
Hypertension should be controlled below 130/80mmHg
.
General kidney protection measures (such as avoiding non-steroidal anti-inflammatory drugs) cannot be overemphasized
.
The status of vaccination should be investigated, and patients should be vaccinated with attenuated vaccines accordingly
.
Vaccination against influenza and Streptococcus pneumoniae is strongly recommended.
Regarding vaccination against shingles, existing data show that the use of live attenuated vaccines (available in most countries) for lupus patients is safe
.
This decision should be individualized, taking into account the patient’s age and immunosuppression status
.
Patients with less immunosuppression may be more suitable for vaccination
.

    The renin-angiotensin-aldosterone system blocker (in non-pregnant patients) is recommended because it has anti-proteinuria and hypotensive effects ; it should be used with caution in patients with impaired renal function
.
Hypertension should be controlled below 130/80mmHg
.
General kidney protection measures (such as avoiding non-steroidal anti-inflammatory drugs) cannot be overemphasized
.
The status of vaccination should be investigated, and patients should be vaccinated with attenuated vaccines accordingly
.
Vaccination against influenza and Streptococcus pneumoniae is strongly recommended.
Regarding vaccination against shingles, existing data show that the use of live attenuated vaccines (available in most countries) for lupus patients is safe
.
This decision should be individualized, taking into account the patient’s age and immunosuppression status
.
Patients with less immunosuppression may be more suitable for vaccination
.
Anti-proteinuria and antihypertensive effects Lupus patients are safe to use live attenuated vaccines (available in most countries)

   The treatment of statins should be determined based on blood lipid levels and whether there are other cardiovascular risk factors
.
It is recommended to use the systemic coronary risk assessment QRisk3 or other validation scores to calculate the 10-year cardiovascular disease risk to help make this decision, considering that these scores may underestimate the actual risk, especially in young SLE patients
.
It is recommended to use low-dose aspirin to prevent thrombosis in the presence of high-risk APL characteristics, and to balance the risk of thrombosis and bleeding
.
According to the risk of fracture, bone protection and prevention of osteoporosis should follow non-pharmacological (exercise intake, maintenance of normal body mass index) and pharmacological measures
.

   The treatment of statins should be determined based on blood lipid levels and whether there are other cardiovascular risk factors
.
It is recommended to use the systemic coronary risk assessment QRisk3 or other validation scores to calculate the 10-year cardiovascular disease risk to help make this decision, considering that these scores may underestimate the actual risk, especially in young SLE patients
.
It is recommended to use low-dose aspirin to prevent thrombosis in the presence of high-risk APL characteristics, and to balance the risk of thrombosis and bleeding
.
According to the risk of fracture, bone protection and prevention of osteoporosis should follow non-pharmacological (exercise intake, maintenance of normal body mass index) and pharmacological measures
.
It is recommended to use low-dose aspirin to prevent thrombosis in the presence of high-risk APL characteristics, and to balance the risk of thrombosis and bleeding
.

5.
Monitoring and prognosis of lupus nephritis

5.
Monitoring and prognosis of lupus nephritis

   The center should evaluate the patients regularly, and the urine microscopy, serology and histology should be checked by experienced clinicians
.
The dynamic changes of proteinuria and serum creatinine in the first 6-12 months are more sensitive than hematuria
.
Quantification of proteinuria can be done by UPCR, because in most studies, it has a high correlation with 24-hour urine protein (although the correlation is low when urine protein is <1000 mg/24 hours)
.
Prior to treatment, 24-hour urine protein may be the first choice
.
A urine test should be included with each visit
.
The reappearance of glomerular hematuria or cell casts can predict impending nephritis
.
Serum C3/C4 and anti-dsDNA should be monitored.
Although the increase in anti-dsDNA titer is related to the occurrence of nephritis , the specificity is not high .
Anti-C1q antibody has the highest correlation with active LN and can also predict recurrence .

   The center should evaluate the patients regularly, and the urine microscopy, serology and histology should be checked by experienced clinicians
.
The dynamic changes of proteinuria and serum creatinine in the first 6-12 months are more sensitive than hematuria
.
Quantification of proteinuria can be done by UPCR, because in most studies, it has a high correlation with 24-hour urine protein (although the correlation is low when urine protein is <1000 mg/24 hours)
.
Prior to treatment, 24-hour urine protein may be the first choice
.
A urine test should be included with each visit
.
The reappearance of glomerular hematuria or cell casts can predict impending nephritis
.
Serum C3/C4 and anti-dsDNA should be monitored, although the increase in anti-dsDNA titer and the dynamic changes of proteinuria and serum creatinine in the 6-12 months before
nephritis are more sensitive than hematuria .
The correlation of 24-hour urine protein is very high.
Each visit should include a urine test for glomerular hematuria or the reappearance of cell casts to predict impending nephritis
.
Serum C3/C4 and anti-dsDNA should be monitored.
The increase in anti-dsDNA titer is related to the occurrence of nephritis , but the specificity is not high .
Anti-C1q antibody has the highest correlation with active LN and can also predict recurrence .
The anti-C1q antibody has the highest correlation with active LN and can also predict recurrence
.

6.
Antiphospholipid syndrome and lupus nephritis

6.
Antiphospholipid syndrome and lupus nephritis

   Antiphospholipid syndrome-associated nephropathy is a rare and unique vascular nephropathy induced by acute promyelocytic leukemia
.
Although TMA is considered to be a sign of antiphospholipid syndrome-related nephropathy, TMA is not etiological, because similar lesions are in thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, malignant hypertension, or complement-mediated It is also found in the TMA
.
There are no controlled studies to guide the treatment of antiphospholipid syndrome-related nephropathy
.
In addition to HCQ, it is also recommended to use antiplatelet drugs or anticoagulants (if it meets the criteria for antiphospholipid syndrome)
.
Blocking the renin-angiotensin-aldosterone system may delay disease progression
.

   Antiphospholipid syndrome-associated nephropathy is a rare and unique vascular nephropathy induced by acute promyelocytic leukemia
.
Although TMA is considered to be a sign of antiphospholipid syndrome-related nephropathy, TMA is not etiological, because similar lesions are in thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, malignant hypertension, or complement-mediated It is also found in the TMA
.
There are no controlled studies to guide the treatment of antiphospholipid syndrome-related nephropathy
.
In addition to HCQ, it is also recommended to use antiplatelet drugs or anticoagulants (if it meets the criteria for antiphospholipid syndrome)
.
Blocking the renin-angiotensin-aldosterone system may delay disease progression
.
Acute promyelocytic leukemia induced vascular nephropathy with antiplatelet drugs or anticoagulants (if it meets the criteria for antiphospholipid syndrome)
.
Blocking the renin-angiotensin-aldosterone system may delay disease progression

Original source

Original source

Fanouriakis A, Kostopoulou M, Cheema K,et al,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.
Ann Rheum Dis 2020 06;79(6)

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