Lupus nephritis (LN) is extremely heterogenous with most patients responding to standard immunosuppressive therapy within 6–12 months. Post hoc analyses suggest that proteinuria at 12 months represents the best single predictor for long-term renal outcome (i.e., risk for end-stage kidney disease (ESKD) or doubling of serum creatine after 10 years). Accordingly, therapy should aim for proteinuria reduction to below 0.7 gm-1/day by 12 months (complete renal response) with patients with nephrotic range proteinuria reaching this milestone for later, by approximately 24 months. Even patients without a complete response at 12–24 months (defined as proteinuria below 1 gm/day and stable creatinine) have an excellent 10-year prognosis.

Based on the above, rushing into using novel therapies from the beginning has the risk of overtreating the vast majority of patients. This is especially true for patients that receive cyclophosphamide as initial induction therapy whereby the benefit of adding biologics such as belimumab is not clear. Of course, people argue that the use of belimumab in such cases may allow faster tapering of glucocorticoids and decrease the risk for renal flares with an added benefit for extrarenal lupus. Another argument often being cited is that even in complete renal responses repeat renal biopsy after therapy shows residual histologic activity.

Still most patients will not flare and identification of those at risk for flare can be done better after initial therapy. Moreover, the clinical significance of histologic activity in complete responders is not clear with only a few of these patients eventually showing evidence of clinical flare. Consistently reported risk factors for a higher disease flare rate include younger age at disease onset, no use of antimalarials, persistent generalized disease activity and serological activity (anti-dsDNA, low complement). Accordingly, in stable patients with improving proteinuria I would consider adding novel therapies after the first year if there is residual proteinuria at the 1–2 gm/day range especially in the presence of risk-factors for flares as defined above.

What do we do for patients with refractory or partial responding disease? According to the 2019 EULAR EDTA recommendations¹ following failure of first line therapy, all remaining first-line therapies including mycophenolate mofetil (MMF)/mycophenolic acid (MPA) (2–3 g/day), cyclophosphamide (CY) and calcineurin inhibition (CNI) (especially tacrolimus) as monotherapy or ‘multitarget’ therapy, are recommended. B-cell depleting therapies such as rituximab, although off-label, are also indicated either as monotherapy or as add-on therapy to MMF/MPA or CY; complete depletion of circulating B-cells predicted clinical remission at 76 weeks. This has recently been supported by a successful trial of obinutuzumab.² Following a response to rituximab, relapses are not uncommon, but occur after a variable length of time. Repeat dose can be considered to prevent or treat a relapse. Finally, belimumab, when added to standard-of-care (including MMF or CY), may gradually reduce proteinuria and the risk for kidney flares.

Learning Objectives

• Explain the treatment goals in lupus nephritis and their rationale

• Describe initial therapy and define refractory or residual disease

• Discuss the pros and cons of early vs late introduction of novel agents as add-on regimens in standard therapy

References

1. 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;79(6):713–23.

2. Marinov AD, Wang H, Bastacky SI, et al. The Type II anti-CD20 Antibody Obinutuzumab (GA101) is More Effective than Rituximab at Depleting B Cells and Treating Disease in a Murine Lupus Model. Arthritis Rheumatol. 2020.