What are the EULAR (European League Against Rheumatism) recommendations for the management of lupus nephritis?

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

The 2019 EULAR/ERA-EDTA recommendations for lupus nephritis management focus on mycophenolate mofetil (MMF) or low-dose intravenous cyclophosphamide combined with glucocorticoids as first-line induction therapy, followed by maintenance with MMF or azathioprine, with treatment targets of complete response by 12 months. 1

Overarching Principles

• Lupus nephritis (LN) requires a multidisciplinary approach involving rheumatologists and nephrologists, with histological confirmation by a nephropathologist 1
• Management in centers with expertise is recommended due to the complexity of the disease 1
• Patient education about the nature, course, and treatment options is essential for shared decision-making 1

Diagnosis and Assessment

• Kidney biopsy is recommended for all patients with clinical evidence of active LN, especially with first presentation 1
• Classification according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) should be used 1
• Risk stratification should incorporate demographic, clinical, and histological data to guide treatment decisions 1

Treatment Goals

• Complete clinical response: proteinuria <0.5-0.7 g/24 hours with normal or near-normal GFR by 12 months 1
• Early response indicators: at least 25% reduction in proteinuria by 3 months and 50% by 6 months 1
• For patients with baseline nephrotic-range proteinuria, the timeframe for complete response may be extended by 6-12 months 1

Initial Treatment Recommendations

Class III or IV (±V) Lupus Nephritis

• First-line options (with the best efficacy/toxicity ratio):
  • MMF (target dose: 2-3 g/day or MPA at equivalent dose) OR
  • Low-dose intravenous cyclophosphamide (500 mg every 2 weeks for a total of 6 doses) 1
• Both should be combined with glucocorticoids:
  • Initial IV methylprednisolone pulses (total dose 500-2500 mg)
  • Followed by oral prednisone (0.3-0.5 mg/kg/day), tapered to ≤7.5 mg/day by 3-6 months 1
• For patients with adverse prognostic factors (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation):
  • Consider high-dose intravenous cyclophosphamide (0.5-0.75 g/m² monthly for 6 months) 1
  • Alternatively, combination of MMF (1-2 g/day) with a calcineurin inhibitor (especially tacrolimus) 1, 2

Class V Lupus Nephritis (Membranous)

• For pure class V with nephrotic-range proteinuria:
  • MMF (target dose 2-3 g/day) with glucocorticoids is preferred 1
  • Alternatives include intravenous cyclophosphamide or calcineurin inhibitors (especially tacrolimus) in monotherapy or combined with MMF 1

Adjunct Treatments

• Hydroxychloroquine should be co-administered in all patients (dose not exceeding 5 mg/kg/day, adjusted for GFR) with regular ophthalmological monitoring 1
• Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for patients with UPCR >500 mg/g or hypertension 1
• Statins for persistent dyslipidemia based on lipid levels and cardiovascular risk assessment 1
• Consider calcium/vitamin D supplementation and/or antiresorptive agents for bone protection 1

Maintenance Therapy

• After achieving improvement with initial treatment:
  • MMF (1-2 g/day) or azathioprine (2 mg/kg/day) for at least 3-5 years 1
  • Low-dose prednisone (2.5-5 mg/day) when needed to control disease activity 1
• Patients who responded to MMF should remain on MMF unless pregnancy is contemplated 1
• For planned pregnancy, switch from MMF to azathioprine at least 3-6 months before conception 1
• Gradual withdrawal can be attempted after at least 3-5 years of complete clinical response (glucocorticoids first, then immunosuppressives) 1
• Hydroxychloroquine should be continued long-term 1

Management of Refractory Disease

• If treatment goals are not achieved, evaluate possible causes including medication adherence 1
• Options for non-responding/refractory disease:
  • Switch from MMF to cyclophosphamide or vice versa 1
  • Consider rituximab (1000 mg on days 0 and 14) 1
  • For pure class V nephritis, consider adding or switching to calcineurin inhibitors 1, 2

Monitoring

• Regular monitoring should include:
  • Body weight, blood pressure, serum creatinine, eGFR, serum albumin
  • Proteinuria, urinary sediment, serum C3 and C4, anti-dsDNA antibody levels
  • Complete blood count 1
• Visits should be scheduled every 2-4 weeks for the first 2-4 months after diagnosis or flare, then according to response 1
• Lifelong monitoring for renal and extra-renal disease activity at least every 3-6 months 1
• Repeat renal biopsy may be considered in cases of worsening or refractory disease 1

Pregnancy Considerations

• Pregnancy may be planned in stable patients with inactive LN (UPCR <500 mg/g for preceding 6 months, GFR >50 mL/min) 1
• Compatible medications (hydroxychloroquine, prednisone, azathioprine, calcineurin inhibitors) should be continued throughout pregnancy 1
• MMF should be withdrawn at least 3-6 months before conception 1
• Acetylsalicylic acid is recommended during pregnancy to reduce pre-eclampsia risk 1
• Pregnant patients should be assessed at least every 4 weeks by a multidisciplinary team 1

Pediatric Considerations

• LN in children is more common at presentation and often more severe 1
• Diagnosis, management, and monitoring principles are similar to adults 1
• A coordinated transition program to adult specialists is essential for long-term adherence and outcomes 1

Common Pitfalls and Caveats

• Delaying immunosuppressive therapy while waiting for serological markers to improve can lead to irreversible kidney damage 1
• Premature switching of therapy before allowing adequate time for response, especially in patients with baseline nephrotic-range proteinuria 1
• Inadequate duration of maintenance therapy increasing risk of flares 1
• Discontinuing hydroxychloroquine, which is associated with reduced flare rates and damage accrual 1
• Failing to adjust medication doses for renal function 1
• Overlooking non-lupus causes of kidney disease that may require different management 1