What are the evidence‑based adverse effects of belimumab in adults with active, autoantibody‑positive systemic lupus erythematosus refractory to standard therapy?

Evidence-Based Adverse Effects of Belimumab in Adults with Active, Autoantibody-Positive SLE

Belimumab demonstrates an acceptable safety profile with balanced adverse events compared to placebo, though clinicians must monitor for slightly elevated risks of psychiatric events (serious depression, suicidality) and infusion/hypersensitivity reactions. 1, 2, 3

Common Adverse Reactions (≥3% incidence)

The most frequently reported adverse reactions in controlled trials include 2:

• Gastrointestinal symptoms: Nausea (15% vs 12% placebo), diarrhea (12% vs 9% placebo) 2
• Constitutional symptoms: Pyrexia (10% vs 8% placebo) 2
• Respiratory infections: Nasopharyngitis (9% vs 7% placebo), bronchitis (9% vs 5% placebo), pharyngitis (5% vs 3% placebo) 2
• Neuropsychiatric: Insomnia (7% vs 5% placebo), depression (5% vs 4% placebo), migraine (5% vs 4% placebo) 2
• Musculoskeletal: Pain in extremity (6% vs 4% placebo) 2
• Genitourinary: Cystitis (4% vs 3% placebo) 2
• Hematologic: Leukopenia (4% vs 2% placebo) 2
• Other infections: Gastroenteritis viral (3% vs 1% placebo) 2

Infections

Overall Infection Risk

• General SLE trials: Overall infection incidence was 71% with belimumab versus 67% with placebo 2
• Lupus nephritis trials: Higher infection rates observed (82% belimumab vs 76% placebo) 2
• Most frequent infections (>5%): upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, influenza 2

Serious Infections

• General SLE trials: Serious infections occurred in 6.0% belimumab versus 5.2% placebo 2
• Lupus nephritis trials: Higher rates (14% belimumab vs 17% placebo) 2
• Large postmarketing safety trial (BASE, N=4,003): Serious infections 3.7% belimumab versus 4.1% placebo 2, 3
• Most common serious infections: pneumonia, urinary tract infections, cellulitis, bronchitis 2
• Opportunistic infections: Recognized risk, particularly CMV infection in immunosuppressed patients 4, 5

Fatal Infections

• General SLE trials: 0.3% (4/1,458) belimumab versus 0.1% (1/675) placebo 2
• Lupus nephritis trials: 0.9% (2/224) in both groups 2
• BASE trial: 0.45% (9/2,002) belimumab versus 0.15% (3/2,001) placebo 2, 3

Hypersensitivity and Infusion Reactions

Hypersensitivity reactions occurred in 13% of belimumab-treated patients versus 11% placebo, with anaphylaxis in 0.6% versus 0.4% placebo. 2

• Manifestations include: hypotension, angioedema, urticaria or other rash, pruritus, dyspnea 2
• BASE trial findings: Higher proportion with serious infusion/hypersensitivity reactions (0.40% belimumab vs 0.10% placebo; difference 0.30%, 95% CI 0.01 to 0.61) 3
• Reactions can be severe and sometimes late-onset 5

Psychiatric Adverse Events

The most concerning safety signal involves psychiatric events, particularly in the large BASE safety trial. 1, 3

Serious Depression

• BASE trial: 0.35% belimumab versus 0.05% placebo (difference 0.15%, 95% CI 0.02% to 0.58%) 1, 3
• Pooled analysis (4,170 patients): 0.2% belimumab versus 0.1% placebo 1

Suicidality and Self-Injury

• Treatment-emergent suicidality: 1.42% belimumab versus 1.16% placebo (difference 0.26%, 95% CI -0.44% to 0.96%) 1, 3
• Sponsor-adjudicated serious suicide or self-injury: 0.75% belimumab versus 0.25% placebo (post hoc difference 0.50%, 95% CI 0.06% to 0.94%) 1, 3
• Suicide/self-injury in pooled analysis: Similar rates (0.3% in each group) 1
• Psychiatric events including suicidal tendency have been reported in post-marketing surveillance 6

Mortality

All-cause mortality rates are low and similar between belimumab and placebo across trials. 3, 7

• BASE trial: 0.50% (10/2,002) belimumab versus 0.40% (8/2,001) placebo (difference 0.10%, 95% CI -0.31 to 0.51) 3
• Pooled RCT data: Peto odds ratio 1.15 (95% CI 0.41 to 3.25); 9/1,714 belimumab versus 6/1,203 placebo 7
• Mortality was rare and may not differ between groups 7

Malignancies

Cancer incidence appears similar between belimumab and placebo. 3

• Non-melanoma skin cancers: 0.20% belimumab versus 0.15% placebo (difference 0.05%, 95% CI -0.21 to 0.31) 3
• Other malignancies: 0.25% in both groups (difference 0.00%, 95% CI -0.31 to 0.31) 3
• Progressive multifocal leukoencephalopathy has been reported 6

Treatment Discontinuation

Discontinuation rates due to adverse events are similar or slightly lower with belimumab. 2

• Overall discontinuation: 6.2% belimumab versus 7.1% placebo 2
• Most common reasons (≥1%): infusion reactions (1.6% belimumab vs 0.9% placebo), lupus nephritis (0.7% vs 1.2%), infections (0.7% vs 1.0%) 2

Long-Term Safety

Belimumab has been studied for up to 13 years with no new safety concerns emerging over time. 8, 9, 10

• Sustained safety profile maintained during extended treatment 10
• Low rates of immunogenicity 10

Important Clinical Caveats

Risk Factors for Adverse Events

• Severe neutropenia (<500 cells/µL), severe lymphopenia (<500 cells/µL), and low IgG (<500 mg/dL) are principal risk factors for infections in SLE patients receiving belimumab 4
• Combination with other immunosuppressants increases infection risk 5

Comparative Safety with Other Biologics

• Unlike rituximab, belimumab appears to have no significant impact on vaccine immunogenicity 1
• Belimumab does not cause the profound B-cell depletion seen with rituximab 1

Lupus Nephritis-Specific Safety

• In BLISS-LN trial, adverse events were balanced between belimumab and placebo groups 1
• Add-on belimumab did not increase adverse event incidence in lupus nephritis trials 8