Lupus Treatment Update: Belimumab, Anifrolumab, and Voclosporin Transform SLE Management

Why Was Belimumab a Breakthrough for Lupus Treatment?

Before belimumab's approval, the last medication specifically approved for lupus was hydroxychloroquine in 1955, creating a 56-year gap in dedicated SLE drug development. Belimumab (Benlysta), developed by Human Genome Sciences and GlaxoSmithKline, is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), also known as B-cell activating factor (BAFF). BLyS is a cytokine critical for B-cell survival, maturation, and differentiation. Elevated BLyS levels are found in SLE patients and correlate with disease activity and autoantibody titers.

The pivotal BLISS-52 and BLISS-76 randomized, double-blind, placebo-controlled trials enrolled over 1,600 seropositive SLE patients. Both trials demonstrated that belimumab, when added to standard therapy, significantly improved SRI-4 response rates (a composite measure of disease improvement) compared to placebo: 57.6% vs 43.6% in BLISS-52 and 43.2% vs 33.5% in BLISS-76 at 52 weeks. Belimumab also reduced severe flares by 38% and allowed greater steroid dose reduction.

In 2020, belimumab received a landmark additional FDA approval for the treatment of active lupus nephritis in adults, based on the BLISS-LN trial. This study demonstrated that adding belimumab to standard therapy (mycophenolate mofetil or cyclophosphamide induction followed by azathioprine) significantly improved complete renal response rates at 2 years (43% vs 32%, p=0.03). Belimumab is now available as both a monthly intravenous infusion and a weekly subcutaneous injection, with a subcutaneous formulation also approved for pediatric patients aged 5 and older.

How Does Anifrolumab Target the Interferon Pathway in Lupus?

Type I interferons play a central role in SLE pathogenesis. Approximately 60-80% of adult SLE patients demonstrate an elevated interferon gene signature (IFNGS) in blood, which correlates with disease activity, organ damage, and poor outcomes. The interferon pathway drives dendritic cell activation, autoantibody production, and tissue inflammation in lupus. Anifrolumab (Saphnelo) is a human monoclonal antibody that binds to the type I interferon alpha receptor subunit 1 (IFNAR1), blocking the signaling of all type I interferons (IFN-alpha, IFN-beta, IFN-omega, and others).

The TULIP-2 trial, the pivotal study for FDA approval, was a phase 3, randomized, double-blind trial of 362 patients with moderate to severe SLE receiving standard therapy. Anifrolumab 300 mg IV every 4 weeks achieved the primary endpoint: BICLA response at week 52 was 47.8% versus 31.5% with placebo (p=0.001). BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) is a comprehensive measure requiring improvement across multiple organ domains. Additionally, 51.5% of patients on anifrolumab reduced their glucocorticoid dose to 7.5 mg/day or below, compared to 30.2% on placebo.

Anifrolumab received FDA approval in July 2021 for moderate to severe SLE. The most common adverse effect was herpes zoster infection (7.2% vs 1.1% with placebo), consistent with the known role of type I interferons in antiviral defense. Patients should receive herpes zoster vaccination before starting treatment. Notably, TULIP-1, the first phase 3 trial, did not meet its primary endpoint (SRI-4 response), but post hoc analyses and the TULIP-2 results using the BICLA endpoint demonstrated consistent efficacy. Subgroup analyses showed enhanced benefit in patients with high IFNGS, suggesting potential for a precision medicine approach.

What New Treatments Are Available for Lupus Nephritis?

Lupus nephritis (LN), affecting up to 50% of SLE patients during their disease course, is one of the most serious manifestations of lupus. Despite treatment with mycophenolate mofetil (MMF) or cyclophosphamide as standard of care, only 20-30% of patients achieve complete renal response at 6-12 months, and 10-30% progress to end-stage kidney disease within 15 years. The approval of voclosporin and the expanded indication for belimumab in lupus nephritis represented major advances in addressing this unmet need.

Voclosporin (Lupkynis), developed by Aurinia Pharmaceuticals, is a novel calcineurin inhibitor (CNI) structurally related to cyclosporine but with improved pharmacokinetic properties including a more predictable dose-response relationship, shorter half-life, and no need for therapeutic drug monitoring. The AURORA 1 trial randomized 357 patients with active lupus nephritis (class III, IV, or V) to receive voclosporin 23.7 mg twice daily or placebo, both added to MMF and low-dose corticosteroids. At 52 weeks, complete renal response (urine protein-to-creatinine ratio of 0.5 mg/mg or below, stable eGFR, and low-dose steroids) was achieved in 41% of voclosporin-treated patients versus 23% with placebo (OR 2.65, p<0.001).

The AURORA 2 extension study confirmed sustained efficacy and safety over 3 years of continued treatment. Voclosporin was FDA-approved in January 2021, specifically for adults with active lupus nephritis in combination with background immunosuppressive therapy. Key safety considerations include monitoring for hypertension, nephrotoxicity (as with all CNIs), and infectious complications. Current lupus nephritis guidelines (EULAR/ERA-EDNA 2023) now include voclosporin and belimumab as add-on options to mycophenolate-based induction therapy, offering clinicians multiple targeted approaches to this challenging disease manifestation.