29 Anti-BAFF receptor therapy (ianalumab) in sjögren’s disease

Sjögren’s disease (SjD) is a chronic, systemic autoimmune disease characterized by exocrinopathy, extraglandular inflammation, and marked B-cell activation. Dryness, fatigue, pain, systemic organ involvement, and increased lymphoma risk contribute to substantial morbidity and impaired quality of life, while therapeutic options in many settings remain largely symptomatic. 1Ianalumab (VAY736) is a fully human IgG1 monoclonal antibody targeting the B-cell activating factor receptor (BAFF-R). Its dual mechanism combines blockade of BAFF-R-mediated survival signalling with enhanced antibody-dependent cellular cytotoxicity, enabling depletion of BAFF-R-positive B cells and direct interruption of a central pathogenic pathway in SjD.2Clinical development has provided convergent evidence for this therapeutic concept. An initial randomized Phase II study in active primary Sjögren’s syndrome demonstrated biologic activity consistent with BAFF-R blockade and B-cell depletion.2A subsequent international, randomized, double-blind, placebo-controlled Phase 2b dose-finding trial enrolled 190 adults with moderate-to-severe disease and demonstrated a dose-response in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) improvement at Week 24, supporting subcutaneous ianalumab 300 mg every 4 weeks as the key regimen for further evaluation.3 Extended follow-up showed sustained efficacy through Week 52 in patients continuing 300 mg, with a generally favourable safety profile.4The global NEPTUNUS phase 3 program evaluated subcutaneous ianalumab 300 mg in adults with active SjD classified according to ACR/EULAR criteria.5 NEPTUNUS-1 randomized 275 patients to monthly ianalumab or placebo, while NEPTUNUS-2 randomized 504 patients to monthly ianalumab, every-3-month ianalumab, or placebo for up to 52 weeks. Monthly ianalumab met the primary endpoint in both studies, demonstrating statistically significant improvement versus placebo in change from baseline in ESSDAI at Week 48. Secondary physician- and patient-reported outcomes generally favored ianalumab, and the overall incidence of adverse events and serious adverse events was comparable with placebo.6Together, the Phase 2b and Phase 3 data support BAFF-R targeting with ianalumab as a rational and clinically active B-cell-directed strategy for systemic SjD. Pending peer-reviewed publication of the full Phase 3 data and continued long-term safety follow-up, ianalumab may represent an important advance for patients with active, systemic disease.Learning Objectives Describe how ianalumab’s dual mechanism of BAFF-R blockade and enhanced antibody-dependent cellular cytotoxicity address B-cell-driven pathogenesis in SjD.Identify the clinical features and trial-entry criteria which define the active systemic SjD population studied in the ianalumab Phase 2b and NEPTUNUS Phase 3 programmes.Explain the efficacy and safety findings that support monthly subcutaneous ianalumab 300 mg as the key regimen evaluated in SjD.Discuss the evidence gaps that remain before ianalumab can be fully integrated into clinical practice, including long-term safety, patient selection, glandular outcomes, and real-world implementation.References Mariette X, Criswell LA. Primary sjögren’s syndrome. N Engl J Med. 2018;378(10):931–39. doi: 10.1056/NEJMcp1702514.Dörner T, Posch MG, Li Y, et al. Treatment of primary Sjögren’s syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis. 2019;78(5):641–47. doi: 10.1136/annrheumdis-2018-214720.Bowman SJ, Fox R, Dörner T, et al. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren’s syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet. 2022;399(10320):161–71. doi: 10.1016/s0140-6736(21)02251-0.Dörner T, Bowman SJ, Fox R, et al. Safety and efficacy of ianalumab in patients with sjögren’s disease: 52-week results from a randomized, placebo-controlled, phase 2b dose-ranging study. Arthritis Rheumatol. 2025;77(5):560–70. doi: 10.1002/art.43059.Shiboski CH, Shiboski SC, Seror R, et al. 2016 American college of rheumatology/European league against rheumatism classification criteria for primary sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 2017;69(1):35–45. doi: 10.1002/art.39859.Grader-Beck T, Mariette X, Finzel S, et al. Ianalumab demonstrates significant reduction in disease activity in patients with Sjögren’s disease: efficacy and safety results from two global phase 3, randomized, placebo-controlled double-blind studies (NEPTUNUS-1 and NEPTUNUS-2). ACR Convergence 2025; Abstract LB24.