Belimumab Linked to Low 5-Year SLE Mortality, With Ronald van Vollenhoven, MD, PhD

Nearly 3000 patients with systemic lupus erythematosus (SLE) were followed for up to 5 years in routine care. Among them, deaths were uncommon with belimumab plus standard therapy, occurring at numerically lower rates than with standard therapy built around conventional immunosuppressants.¹

Ronald F. van Vollenhoven, MD, PhD, chair of the Department of Rheumatology and Clinical Immunology at Amsterdam UMC and director of the Amsterdam Rheumatology and Immunology Center, presented the analysis from the global, prospective, non-randomized SABLE registry at the American College of Rheumatology (ACR) Convergence 2026 in Orlando, Florida, and discussed the findings in an interview with HCPLive.

Because the study was observational, the findings add long-term, real-world mortality data to the safety profile of the B-lymphocyte stimulator (BLyS) inhibitor but cannot establish a survival benefit with belimumab.

Excess Mortality in SLE and Long-Term Belimumab Safety

Despite advances in management, patients with SLE continue to experience higher mortality than the general population, with a reported standardized mortality ratio of 2.65 (95% confidence interval [CI], 2.13–3.26). Cardiovascular disease and neoplasms account for approximately half of deaths, while glucocorticoid exposure, uncontrolled disease activity, and infections also contribute to excess mortality.¹

“Mostly they do not die from their lupus. It can happen, and we still need to get better at treating lupus,” van Vollenhoven said. “But we are also seeing increases in mortality compared to the healthy individual that have to do with an increased risk for infection, probably in large part due to the treatment, maybe also cardiovascular disease.”

Belimumab is approved by the US Food and Drug Administration (FDA) for patients aged ≥5 years with active SLE or active lupus nephritis who are receiving standard therapy.²

The European Medicines Agency (EMA) required SABLE as a condition of belimumab's marketing authorization to characterize long-term risks beyond clinical trials.³ The registry's broader 5-year safety findings were presented at the 15th European Lupus Meeting (SLEuro 2026). In the initial-exposure analysis, serious infections and serious psychiatric events occurred at numerically higher rates with belimumab, although most adverse events of special interest were similar or numerically lower in the belimumab group when treatment switching was accounted for.⁴

The current analysis focused specifically on mortality and its leading causes.

Van Vollenhoven said the findings did not change which patients he would start on belimumab. Instead, they increased his confidence in prescribing it.

“I think the fair answer is that it didn’t so much help me with the decision, but I think it gave me more comfort with the decision as a prescribing physician,” he said. “You will have to see the efficacy for each individual person, but you can be confident that they will at least be okay.”

His comments reflect greater prescribing confidence based on the observed mortality findings, rather than evidence of a guaranteed safety outcome or survival benefit.

How SABLE Assessed Belimumab Exposure and Mortality

SABLE (NCT01729455) enrolled adults with active, autoantibody-positive SLE from 2013 to 2020 and followed them for up to 5 years, with safety data collected at 6-month intervals.¹˒⁵ Patients received either belimumab plus standard therapy, with or without immunosuppressants, or standard therapy plus immunosuppressants without belimumab. Patients could be starting treatment or already receiving it when they enrolled.

Because patients in routine care may switch therapies over 5 years, investigators analyzed mortality using 3 exposure strategies:

• Initial exposure (intent-to-treat): Patients were classified according to their treatment at baseline.
• As-exposed: A time-varying analysis accounted for treatment switching after enrollment, with a 14-week or 6-month washout period after the last belimumab dose.
• Ever-exposed: Patients were classified as belimumab-exposed if they received the treatment at any point after enrollment.¹

The different strategies allowed investigators to examine whether the observed mortality patterns were consistent when accounting for changes in treatment exposure.

Five-Year Mortality and Leading Causes of Death in SABLE

The registry included 2967 patients, with 2030 in the belimumab group and 937 in the non-belimumab group. Baseline characteristics were generally similar, although a greater proportion of patients receiving belimumab had other concomitant autoimmune disorders and psychiatric disorders.¹

All-cause mortality incidence rates per 100 patient-years were numerically lower in the belimumab group across all 3 exposure strategies.

In the initial-exposure analysis, 2.5% of patients in the belimumab group (48 of 1924) died during the 5-year observation period, compared with 3.3% of patients in the non-belimumab group (29 of 881).¹ These denominators represent the patients included in the reported initial-exposure mortality comparison rather than the full registry population.

In the previously presented SABLE safety analysis, the initial-exposure mortality incidence rate was 0.65 (95% CI, 0.48–0.86) per 100 patient-years with belimumab, compared with 0.83 (95% CI, 0.56–1.20) without belimumab.⁴ The numerical difference does not establish a statistically significant or causal reduction in mortality.

The most frequently reported causes of death, classified by system organ class, were:

• Infections and infestations: 0.5% with belimumab vs 1.1% without belimumab
• Cardiac disorders: 0.5% vs 0.6%
• General disorders and administration site conditions: 0.4% vs 0.5%
• Respiratory, thoracic and mediastinal disorders: 0.3% vs 0.6%¹

Van Vollenhoven said none of these categories numerically favored the non-belimumab group. However, the small number of deaths within individual categories limits conclusions about specific causes of mortality.

Interpreting Non-Randomized Belimumab Mortality Data

The investigators acknowledged the observational design and potential residual confounding as limitations to causal inference.¹ Treatment was selected by clinicians rather than assigned randomly, introducing the possibility of channeling bias.

Van Vollenhoven suggested patients receiving belimumab may have had more difficult-to-control disease, potentially placing them at greater baseline risk.

“I think the more logical expectation would be that if you choose belimumab, it’s probably because the patient is not doing so well, and that might make them more at risk for certain things,” he said.

However, treatment selection may also reflect other patient characteristics and clinical considerations. The direction and magnitude of any resulting bias cannot be determined from these findings alone.

Van Vollenhoven identified psychiatric comorbidities as one potential exception to his interpretation. Previous concerns about psychiatric adverse events with belimumab may have influenced treatment selection, although the registry reported a greater baseline prevalence of psychiatric disorders among patients in the belimumab group. The current FDA prescribing information includes warnings concerning depression and suicidality.²

The investigators described the mortality findings as consistent with a previous target trial emulation. That observational study evaluated patients with non-renal SLE and found belimumab initiation was associated with lower all-cause mortality than initiation of azathioprine, methotrexate, or mycophenolate in intention-to-treat analyses, with hazard ratios ranging from 0.40 to 0.61.⁶

Although the findings were directionally consistent, neither observational analysis establishes belimumab as a mortality-reducing treatment. The SABLE investigators concluded that belimumab plus standard therapy may be associated with a low mortality risk in patients with SLE.¹

SABLE began enrolling patients more than a decade ago, and the SLE treatment landscape has continued to evolve. Van Vollenhoven said he expects the mortality findings to remain relevant while emphasizing the need to determine how available and emerging therapies can best be used.

“For the coming years, of course, we’re going to be more and more interested in seeing how belimumab, as well as all the other medications for lupus, can be used in the best possible ways for the benefit of our patients,” he said.

Editor's Note: Van Vollenhoven reports relevant financial relationships with GSK and other pharmaceutical companies. The SABLE registry was funded by GSK.

References

1. van Vollenhoven R, Bruce I, Merrill J, et al. Low Five Year Mortality in SLE Treated with Belimumab: Findings from the Prospective, Global, SABLE Registry [abstract]. Arthritis Rheumatol. 2026;78(suppl 9). Presented at: American College of Rheumatology Convergence 2026; November 6-11, 2026; Orlando, FL. https://acrabstracts.org/abstract/low-five-year-mortality-in-sle-treated-with-belimumab-findings-from-the-prospective-global-sable-registry/

2. Benlysta (belimumab). Prescribing information. GlaxoSmithKline; revised August 2026. Accessed November 8, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761043s039lbl.pdf

3. SABLE: A 5-Year Prospective Observational Registry to Assess Adverse Events of Interest and Effectiveness in Adults with Active, Autoantibody-Positive Systemic Lupus Erythematosus Treated With or Without Benlysta (Belimumab). HMA-EMA Catalogues of Real-World Data Sources and Studies. EUPAS4966. Updated March 9, 2026. Accessed November 8, 2026. https://catalogues.ema.europa.eu/study/45713

4. van Vollenhoven R, Bruce IN, Merrill JT, et al. Five-year safety of belimumab in SLE: insights from the global, prospective, observational SABLE registry [abstract]. Lupus Sci Med. 2026;13(suppl 1). Presented at: 15th European Lupus Meeting; March 4-7, 2026; Lisbon, Portugal. https://lupus.bmj.com/content/13/Suppl_1/A293.2

5. Safety and Effectiveness of BENLYSTA (Belimumab) in Systemic Lupus Erythematosus (SLE) Registry (SABLE). ClinicalTrials.gov identifier: NCT01729455. Accessed November 8, 2026. https://clinicaltrials.gov/study/NCT01729455

6. Lee G, Barmettler S, Zhang L, Jorge A. Comparative Risk of All-Cause Mortality with Belimumab versus Oral Immunosuppressant Use in Patients with Non-Renal Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2025;77(suppl 9). Presented at: American College of Rheumatology Convergence 2025; October 24-29, 2025; Chicago, IL. https://acrabstracts.org/abstract/comparative-risk-of-all-cause-mortality-with-belimumab-versus-oral-immunosuppressant-use-in-patients-with-non-renal-systemic-lupus-erythematosus/