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Lupus nephritis: New predictors of renal outcomes and treatment strategies.

Comment on: Furie R, Rovin BH, Houssiau F, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med 2020; 383:1117-1128. Link:

Commented by: Luís Sousa Inês, MD, PhD. CHUC Lupus Clinic, Rheumatology Department. Centro Hospitalar Universitário de Coimbra (CHUC). Coimbra, Portugal. Faculty of Health Sciences. University of Beira Interior. Covilhã, Portugal.

In this article, Furie et al. report the results of a phase 3, 104-week, randomized, double-blind trial of belimumab as compared with placebo, plus standard therapy [mycophenolate mofetil (MMF) or cyclophosphamide followed by azathioprine, and glucocorticoids], in adults with active lupus nephritis (biopsy-proven, class III, IV and/or V). The intent-to-treat study population included 446 patients recruited from 107 sites in 21 countries (Europe, Asia, and America). For induction, 6 intravenous cyclophosphamide 500 mg pulses were given every 2 weeks, according to the Euro-Lupus regimen3 or mycophenolate mofetil with a target dose of 3 g/day, as chosen by the local investigators. Also, at the investigators’ discretion, 1 to 3 intravenous pulses of methylprednisolone (500-1000 mg each) could be given. Oral prednisone was given at an initial dose up to 60 mg/day, that should be tapered to 10 mg/day or less by week 24. Belimumab was given intravenously at 10 mg/ Kg or placebo at baseline, 15, 29 and every 28 days thereafter up to week 100. Maintenance immunosuppression was given with azathioprine after cyclophosphamide induction or with continuing MMF in the other induction group. Co-medications according to standard-of-care were recommended. At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response [43% vs. 32%; odds ratio (OR) =1.6; 95% confidence interval (CI) =1.0-2.3] and a complete renal response (30% vs. 20%; OR =1.7; 95% CI =1.1-2.7). A higher primary efficacy renal response appeared by week 24 and was generally maintained through week 104. The risk of a renal-related event or death was lower in the group who received belimumab than among those who received placebo (hazard ratio =0.51; 95% CI =0.34-0.77). Infections and other adverse events occurred with similar frequency in both groups.

The success of this phase 3 trial in achieving its primary efficacy renal endpoint is noteworthy. Other strengths include the large study population and follow-up that was longer than previous trials in LN, as well as providing further evidence for the safety of belimumab as an add-on therapy in SLE patients.

There are however some caveats, as pointed out in the accompanying editorial by Ward and Tektonidou.4 No benefit of add-on belimumab was found in the subgroup of patients who received cyclophosphamide-azathioprine. This could be due to several causes, including a small sample size for this subgroup analysis, a lesser efficacy in more severe LN cases or a lack of add-on benefit of belimumab with cyclophosphamide-azathioprine. Of note, the study protocol pragmatically allowed the treating physician to choose the induction regimen for each participant. However, this resulted in imbalances between the cyclophosphamide and MMF induction groups, suggesting that the former included more cases with severe LN. Furthermore, the study protocol did not allow for rescue induction for non-responders, by switching patients from cyclophosphamide to MMF and vice-versa, as recommended for clinical practice, which could have improved the overall response rates in the study population.2

There is a need for further trials to ascertain a potential role of belimumab in treating patients with refractory or relapsing LN. It was recently published a phase 2, multicenter, randomised, open label clinical trial (CALIBRATE) that tested in 43 patients with proliferative LN refractory to standard-of-care, a combination regimen with cyclophosphamide, rituximab, and glucocorticoids, followed by randomisation to belimumab infusions or no infusions until week 48, and patients were followed-up until week 96.5 The combination regimen was found to be safe, which was the primary endpoint. Immunomodulatory mechanisms of action were assessed. No differences in efficacy were found, although the sample size of the CALIBRATE study was not powered for efficacy.


  1. Tektonidou M, Dasgupta A, Ward MM. Risk of End-Stage Renal Disease in Patients With Lupus Nephritis, 1971–2015. A Systematic Review and Bayesian Meta-Analysis. Arthritis Rheum 2016; 68:1432-1441.
  2. 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; 79:713-723.
  3. Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002; 46: 2121-31.
  4. Ward M, and Tektonidou MG. Belimumab as Add-on Therapy in Lupus Nephritis. N Engl J Med 2020; 383:1184-1185.
  5. Atisha-Fregoso Y, Malkiel S, Harris KM, et al. CALIBRATE: A Phase 2 Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Arthritis Rheumatol 2020 Aug 4. [Epub ahead of print] doi: 10.1002/art.41466.