Updated EULAR/ERA-EDTA Recommendations for the Management of Lupus Nephritis

Based on emerging new evidence and expert consensus, a multidisciplinary task force put together by the European League Against Rheumatism (EULAR) and European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) released updated recommendations for the management of lupus nephritis. This report was published in Annals of the Rheumatic Diseases.

Investigators performed a systematic review of studies focused on treatment targets, the use of glucocorticoids and calcineurin inhibitors, and the management of end-stage kidney disease (ESKD) in patients with lupus nephritis. Recommendations were developed using the modified Delphi method, in which the investigators devised related questions and elicited expert opinions before reaching a consensus. 

Overarching Principles

The nature of lupus nephritis is such that it requires a multidisciplinary approach to care by rheumatologists and nephrologists, in a shared decision-making process with patients. The task force recommended that kidney involvement in lupus nephritis be confirmed through histologic assessment by a nephropathologist, and that disease management and periodic evaluation of these patients be performed in specialized centers.

The panel suggested that goals of treatment include patient survival, preservation of kidney function, prevention of disease flares and organ damage, management of comorbidities, and improvements in disease-related quality of life. Management of active lupus nephritis should typically include an initial period of intense immunosuppressive therapy followed by a longer period of less intensive therapy.

Recommendations for Investigation of Suspected Lupus Nephritis

The task force recommended kidney biopsy in patients with systemic lupus erythematosus (SLE) where evidence of kidney involvement is present: glomerular hematuria and/or cellular casts, proteinuria >0.5 g every 24 hours or urine protein-to-creatine ratio (UPCR) ≥500 mg/g, and unexplained decreases in glomerular filtration rate (GFR).

All patients with SLE, especially those with suspected kidney involvement, should be tested for antiphospholipid antibodies (aPL), as findings from this test may have diagnostic and prognostic significance.

Recommendations for Pathologic Assessment of Kidney Biopsy

The task force recommended the 2003 International Society of Nephrology/Renal Pathology Society classification system as the gold standard for assessing kidney biopsy in lupus nephritis. In addition, thrombotic microangiopathy (TMA) lesions may implicate aPL syndrome nephropathy, therefore, patients with TMA lesions should be retested for aPL. The presence of tubulointerstitial lesions, including interstitial fibrosis and tubular atrophy, could be further associated with poor outcomes.

Recommendations for Immunosuppressive Treatment

The task force recommended immunosuppressive therapy in patients with active class 3 or 4 lupus nephritis.

Among patients with pure class 5 lupus nephritis, immunosuppressive treatment can be recommended in cases with nephrotic-range proteinuria or proteinuria >1 g every 24 hours despite optimal renin-angiotensin-aldosterone system blocker use.

Although class 2 lupus nephritis typically does not require immunosuppressive therapy, healthcare providers should ensure histologic reassessment in the presence of significant proteinuria.

Recommendations for Treatment of Adult Lupus Nephritis

Goals of Treatment

According to the task force, goals of treatment should include long-term stabilization of kidney function; improved proteinuria levels by 3 months, and a 50% reduction in proteinuria (partial clinical response) by 6 months. By 12 months, therapy should aim for proteinuria <0.5 to 0.7 g every 24 hours (complete clinical response).

For patients with nephrotic-range proteinuria at baseline, the task force suggested that an additional 6 to 12 months may be required to reach complete clinical response. Because of slower proteinuria recovery in these patients, prompt switching of therapies is not necessary as long as proteinuria is improving.

Initial Treatment

Among patients with class 3 or 4 lupus nephritis, first-line options for induction treatment may include mycophenolate mofetil/mycophenolic acid and low-dose intravenous cyclophosphamide, in combination with glucocorticoids. The recommended target dose of mycophenolate mofetil has been changed to 2 to 3 g per day (or the mycophenolic acid equivalent of 1.44-2.16 g/d), and 500 mg every 2 weeks for a total of 6 doses of low-dose intravenous cyclophosphamide; the task force suggested that these doses may be adjusted according to changes in efficacy or tolerance/adverse effects.

For pure class 5 lupus nephritis, the same first-line options were recommended. In patients with adverse clinical or histologic prognostic factors, high-dose intravenous cyclophosphamide may be considered, of which a monthly dose of 0.5 to 0.75 g/m² has been recommended for 6 months.

The task force recommended lower starting doses of glucocorticoids (≤0.5 mg/kg/d) as they are considered as effective as higher doses. Depending on the severity, the total intravenous methylprednisolone dose should range from 500 to 2500 mg; the starting oral prednisone dose should range from 0.3 to 0.5 mg/kg per day and tapered to ≤7.5 mg per day by 3 to 6 months.

Alternative first-line therapeutic options include calcineurin inhibitors, especially tacrolimus and cyclosporine A, either as monotherapy or in combination with mycophenolate mofetil (or the mycophenolic acid equivalent), may be particularly effective in patients with nephrotic-range proteinuria.

In patients with lupus nephritis, hydroxychloroquine was  recommended by the panel in the absence of contraindications; however, daily doses should be ≤5 mg/kg of body weight and for GFR <30 mL per minute, Patients should be recommended to receive yearly eye screening due to ocular toxicity associated with hydroxychloroquine.

Subsequent Treatment

After an adequate response to initial treatment, subsequent immunosuppressive therapy may be recommended. The task force suggested maintenance with mycophenolate mofetil/mycophenolic acid if it was used as the induction therapy or azathioprine after mycophenolate mofetil/mycophenolic acid induction therapy. Initial treatment with cyclophosphamide may be followed by maintenance therapy with mycophenolate mofetil/mycophenolic acid or azathioprine. Among patients who are contemplating pregnancy, azathioprine is the preferred agent to control disease activity.

According to previous studies, patients with lupus nephritis experience renal flares in the first 5 to 6 years after treatment initiation. The task force recommended against the discontinuation of immunosuppressive therapies until patients have attained sustained complete renal response. Withdrawal of treatment should be gradual, with glucocorticoids tapered first followed by immunosuppressive drugs.  However, patients should continue to receive long-term treatment with hydroxychloroquine.

Among patients with pure class 5 lupus nephritis, calcineurin inhibitor may be considered at the lowest effective dose, after evaluation of nephrotoxicity risks.

Nonresponding/Refractory Disease

Before diagnosis of nonresponding/refractory disease, the task force recommended a thorough assessment of a patient adherence to treatment and monitoring of therapeutic drug levels.

In the case of active nonresponding/refractory disease, any of the first-line therapies, including mycophenolate mofetil/mycophenolic acid, cyclophosphamide, or calcineurin inhibitors, may be considered as monotherapy or “multitarget” therapy. Rituximab (1000 mg every 14 days) may also be indicated as monotherapy or add-on therapy after nonresponse in patients with lupus nephritis.

Recommendations for Adjunct Treatment

Among patients with lupus nephritis with impaired renal function or arterial hypertension (except in pregnancy), renin-angiotensin-aldosterone system blockers were recommended by the task force. Vaccination, particularly against influenza and Streptococcus pneumoniae, was strongly recommended. On the other hand, nonsteroidal anti-inflammatory drugs should be avoided in these patients as they may further damage the kidneys.

Statin therapy use should be based on lipid status and presence of other cardiovascular risk factors; a validated scoring system such as the Systematic Coronary Risk Evaluation or QRisk3 has been recommended to guide this decision.

The task force recommended the prevention of osteoporosis and bone protection measures based on fracture risk, and suggested the inclusion of both nonpharmacologic (exercise, maintaining normal weight) and pharmacologic therapies (supplementation, antiresorptive agents). They recommended the prevention of thrombosis with low-dose aspirin in patients with high-risk aPL profiles and bleeding risk. Belimumab may be considered as an add-on treatment.

Recommendations for Monitoring and Prognosis of Lupus Nephritis

Patients with lupus nephritis should be periodically reassessed in specialty centers; each visit should include urinalysis to measure proteinuria (quantified by spot UPCR or 24-hour urine collection), presence of glomerular hematuria, and cellular casts that are predictors of impending kidney flare. Serum C3/C4 and anti-dsDNA titers should also be monitored at these visits.

Among patients with nonresponse to immunosuppressive treatment or to differentiate between ongoing histologic activity and irreversible damage, a repeat kidney biopsy may be considered. Protocol rebiopsy may be required to determine histologic class transition, changes in activity, or the need for continuous treatment.

Recommendations for Managing ESKD in Lupus Nephritis

The task force recommended that all methods of kidney replacement modalities be considered in patients SLE. However, kidney transplantation was recommended as the preferred method over other options, including hemodialysis or continuous peritoneal dialysis, as it may be associated with a higher survival rate. Transplantation should not be delayed and has been recommended for patients whose extra-renal lupus is clinically inactive for at least 6 months and in the presence of isolated serologic activity. During transplantation preparation, aPLs should be measured.

Recommendations for Antiphospholipid Syndrome and Lupus Nephritis

Among patients with antiphospholipid syndrome-associated nephropathy, the task force recommended treatment with antiplatelet/anticoagulant agents, in addition to hydroxychloroquine. Renin-angiotensin-aldosterone system blockers may also be considered as they can delay disease progression.

Recommendations for Lupus Nephritis and Pregnancy

The task force recommended the 2017 EULAR guidelines for pregnancy planning while managing SLE. Stable patients with inactive lupus nephritis may consider pregnancy; healthcare providers should ensure that UPCR is controlled at levels <500 mg/g for the prior 6 months without renin-angiotensin-aldosterone system inhibitor use, which is contraindicated during the first trimester.

Drugs such as prednisone, azathioprine, calcineurin inhibitors, and hydroxychloroquine are compatible at safe dosages and may be continued during pregnancy and lactation; however, the task force recommended the withdrawal of mycophenolate mofetil/mycophenolic acid 3 to 6 months before attempting conception to provide time to assess the efficacy and tolerability of alternate immunosuppressive treatments.

If lupus nephritis flares occur during pregnancy and patients experience nonresponse to drugs with acceptable safety profiles, the task force recommended that the patient be referred to a multidisciplinary specialist. Acetylsalicyclic acid may be used to reduce risk for pre-eclampsia. 

Recommendations for the Management of Pediatric Patients

Among children vs adults with new-onset lupus nephritis, kidney involvement is more common in SLE. According to the 2012 EULAR/ERA-EDTA recommendations for managing pediatric lupus nephritis, the task force suggested that the diagnosis, treatment (using pediatric doses), and monitoring of children was similar to that of adults. To ensure continued adherence and optimize long-term outcomes, a transition program for children in adolescence may be recommended.

Disclosures: Several study authors declared affiliations with the pharmaceutical industry. Please refer to the original reference for a complete list of authors’ disclosures.

Reference

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 [published online March 27, 2020]. Ann Rheum Dis. doi:10.1136/annrheumdis-2020-216924