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How Would You Manage This Patient With Edema of the Lower Extremities?

  • Correct answer: G. A and B

     

    The renal biopsy showed diffuse proliferative glomerulonephritis with crescents. Lupus nephritis occurs in 12% to 69% of patients with systemic lupus erythematosus and can be a main source of renal-related morbidity.1 The goal of therapy is to prevent long-term chronic kidney disease (CKD) and end-stage renal disease (ESRD). This approach should focus on complete partial reversal of the clinical signs of kidney injury. The accumulation in the kidney of immune complexes already indicates a fairly robust inflammatory process.2

    Treatment of proliferative lupus nephritis is broken down into 2 phases: the induction phase followed by the maintenance phase. Treatment regimens for lupus nephritis incorporate high-dose corticosteroids for rapid control of inflammation and either mycophenolate mofetil (MMF) or cyclophosphamide to control inflammation and potentially reduce adverse renal outcomes.3 These regimens have been well studied. Mycophenolate is the preferred treatment in recent years, because it is reportedly less toxic than cyclophosphamide.  

    Recently, the study of 2 newer agents has caught the attention of the lupus nephritis community. Belimumab is a recombinant human immunoglobulin G-1 (IgG-1) monoclonal antibody that inhibits B-cell activating factor and has shown some promise in studies on lupus nephritis. These studies are the Belimumab in Subjects with Systemic Lupus Erythematosus, or BLISS-52 and BLISS-76.(4) Results of these 2 trials led to the approval of belimumab for treatment for lupus nephritis. Post-hoc analyses involving patients in these trials showed that proteinuria had decreased, and there were fewer renal flares in patients taking belimumab when compared with “standard therapy” including corticosteroids and MMF.4 

    Most recently, BLISS-LN(5) looked at standard therapy, defined as MMF or cyclophosphamide–azathioprine, for active lupus nephritis vs standard therapy and placebo. A total of 448 patients were randomly assigned: 224 to the belimumab group and 224 to the placebo group. Many more patients in the belimumab group had a primary efficacy renal response (43% vs 32%) and a complete renal response (30% vs 20%) at week 104 than in the placebo group. The safety profile was also similar to previous studies.5 These studies, while needing additional support, may allow better renal outcomes over standard therapy when treating lupus nephritis, with the goal of reducing advancing CKD and ESRD risk.

    Voclosporin is another agent that is a calcineurin inhibitor and is similar to tacrolimus. It received approval from the US Food and Drug Administration in January 2021 for treatment of lupus nephritis. (6) The AURORA clinical trial investigators evaluated whether voclosporin, when added to standard therapy of MMF, can accelerate improved renal response rates in the presence of low-dose steroids.6 The primary endpoint for the study was complete renal response at 52 weeks or stable estimated glomerular filtration rate (eGFR). The target enrollment of 324 patients was surpassed with a total of 357 patients with lupus nephritis in 27 different countries. Results of the AURORA trial demonstrated that voclosporin was twice as effective at achieving a complete renal response as the standard treatment. Proteinuria in this group also decreased by 50%.6

    Adjuncts to standard lupus nephritis therapy are important because of the physical and economic impacts of ESRD. Patients with lupus nephritis have a 10-fold higher incidence rate of ESRD than that of patients who do not have lupus nephritis.7 Finding ways to alleviate the progression of lupus nephritis with standard therapy would help treat this difficult disease.   

    References

    1. Wang H, Ren YL, Chang J, Gu L, Sun LY. A systematic review and meta-analysis of prevalence of biopsy-proven lupus nephritis. Arch Rheumatol. 2017;33(1):17-25. https://doi.org/10.5606/archrheumatol.2017.6127
    2. Almaaini S, Meara A, Rovin BH. Update on lupus nephritis. Clin J Am Soc Nephrol.  2017;12(5):825-835. https://doi.org/10.2215/CJN.05780616
    3. Parikh SV, Rovin BH. Current and emerging therapies for lupus nephritis. J Am Soc Nephrol. 2016;27(10):2929-2939. https://doi.org/10.1681/asn.2016040415 
    4. Dooley MA, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus. 2013;22(1):63-72. https://doi.org/10.1177/0961203312465781 
    5. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. New Engl J Med. 2020;383(12):1117-1128. https://doi.org/10.1056/nejmoa2001180
    6. Arriens C, Polyakova S, Adzerikho I, Randhawa S, Solomons N. AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (LN). Ann Rheum Dis. 2020;79(Suppl 1):172-173 http://dx.doi.org/10.1136/annrheumdis-2020-eular.5010
    7. Choi HS, Han KD, Jung JH, et al. The risk of end-stage renal disease in systemic lupus erythematosus: a nationwide population-based study in Korea. Medicine. 2019;98(28):e16420. https://doi.org/10.1097/md.0000000000016420