Belimumab - a well-responded addition for better preservation of renal functions in lupus nephritis

31 Dec 2020

Lupus nephritis is a complication of systemic lupus erythematosus (SLE), an autoimmune disease that induces kidney inflammation and can ultimately lead to end stage renal disease.1,2 Traditionally, the standard treatment for lupus nephritis consists of corticosteroids in combination with intravenous mycophenolate mofetil or cyclophosphamide-azathioprine.1,3 Nevertheless, over the past several decades, the response rate of patients towards these standard therapies remained unacceptably low, which created a need for newer and more favorable options.3 In a recent phase 3 study, the addition of belimumab to current standard treatment had demonstrated superior efficacy and safety than the standard treatment alone.3

Lupus nephritis is one of the many complications of SLE that manifests in 30% of SLE patients.4 Mechanically, lupus nephritis is caused by the loss of central tolerance towards nuclear autoantigens in the kidneys which induces the production of autoantibodies and causes tissue inflammation.5 The inflammation can trigger the release of proinflammatory cytokines and causes a chain reaction of inflammation that targets somatic tissues.5 Prolonged inflammation of kidney tissues can result in the loss of renal function as well as renal failure.2

Belimumab is a B lymphocyte stimulator (BLyS)-specific inhibitor which impedes the binding of BLyS to B-cell receptors.6 By inhibiting BLyS binding, the differentiation of B cells into autoreactive plasma cells can then be blocked, which in turn prevents the production of autoantibodies.6 In the multinational, multicentre, single-blind, phase 3 BLISS-LN study, 446 SLE patients with class III or above lupus nephritis were randomized into receiving either a daily intravenous injection of 10mg/kg belimumab or a matching placebo in addition to standard therapy.3

As early as at week 24, a higher percentage of patients in the belimumab arm achieved a primary renal response, defined as a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate (eGFR) that was no worse than 20% below the value before renal flare or ≥60ml/min/1.73m2, and without the use of rescue therapy.3

The clear therapeutic benefit continued to week 104 with 43% of patients in the belimumab arm achieving primary renal response, whereas only 32% of patients in the placebo arm could achieve the same (OR=1.6; 95% CI: 1.0-2.3; p=0.03).3 Furthermore, 30% of patients in the belimumab arm and only 20% in the placebo arm (OR=1.7; 95% CI: 1.1-2.7; p=0.02) had achieved a complete renal response, defined as a ratio of urinary protein to creatinine <0.5, an eGFR that was no worse than 10% below the value before renal flare or ≥90ml/min/1.73m2, and without the need of rescue therapy.3 When compared to placebo, patients treated with belimumab also had a prominently lower risk of renal-related events or death (HR=0.51, 95% CI: 0.34-0.77, p=0.001).3

While the BLISS-LN study had demonstrated a clear efficacy and safety benefit of belimumab over placebo, the study was limited by having a low enrolment of Black patients and patients receiving cyclophosphamide–azathioprine.3 In addition, there were only two current standard therapies included in the study, while other currently available therapeutic options such as calcineurin inhibitors were not evaluated.3 That said, the safety profile of belimumab was consistent with observations made in previous trials.3 Given its demonstrated efficacy and safety profile, adjuvant belimumab to standard treatment may serve as a potential new generation therapy in the front-line treatment of lupus nephritis.

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