A recent study published in Rheumatic & Musculoskeletal Diseases Open found that upadacitinib monotherapy and combination therapy with elsubrutinib maintained and improved efficacy outcomes in patients with moderately to severely active systemic lupus erythematosus through 104 weeks of treatment.
The long-term extension study followed 127 patients from the 48-week phase 2 SLEek study, evaluating an additional 56 weeks of treatment with upadacitinib 30 mg once daily, either as monotherapy or combined with elsubrutinib 60 mg once daily. Patients originally randomized to upadacitinib monotherapy or combination therapy continued their assigned treatments, while those previously receiving placebo switched to the combination regimen.
Efficacy responses demonstrated sustained or improved outcomes from weeks 48 to 104 across multiple endpoints. At week 104, SLE Responder Index-4 (SRI-4) response rates reached 82.1% for upadacitinib monotherapy, 85.4% for combination therapy, and 61.3% for the placebo-to-combination group. British Isles Lupus Assessment Group-based Combined Lupus Assessment (BICLA) responses were 69.2%, 78.0%, and 54.8%, respectively. Lupus Low Disease Activity State (LLDAS) achievement rates were 60.0%, 78.0%, and 34.4% for the respective treatment groups.
Clinical benefits extended beyond disease activity measures. Mean daily glucocorticoid doses decreased from weeks 48 through 104 across all treatment groups. The incidence of flare events remained stable or further declined during the extension period. Safety profiles remained consistent with those observed in the primary 48-week SLEek study.
Upadacitinib is an oral selective JAK inhibitor that has shown efficacy and acceptable safety across multiple immune-mediated conditions, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, Crohn’s disease, and atopic dermatitis. Elsubrutinib is an oral selective BTK inhibitor developed for autoimmune diseases. Through BTK inhibition, elsubrutinib is thought to suppress B cell activation and immune complex–driven activation of dendritic cells and neutrophils. In contrast, upadacitinib disrupts signaling through type I and type II interferon receptors, T cell activation, and several cytokine pathways implicated in SLE, including interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-15. Together, the ABBV-599 combination (elsubrutinib plus upadacitinib) offers the potential for broader inhibition of SLE pathophysiology than either agent alone.
These findings are particularly relevant given the limited long-term data for SLE therapies and highlight the potential for steroid-sparing regimens and improved organ protection. Overall, the results provide a strong rationale for ongoing phase 3 evaluation of upadacitinib and ABBV-599 combination therapy, and may inform future personalized treatment strategies for patients with moderately to severely active SLE.
References
- Merrill JT, Saxena A, Aringer M, Tanaka Y, Zeng X, Cheng L, Doan TT, D’Cruz D, Masri KR, D’Silva KM. Efficacy and safety of upadacitinib as monotherapy or combined with elsubrutinib for the treatment of systemic lupus erythematosus: results through 104 weeks in a long-term extension study. RMD Open. 2025 Aug 18;11(3):e005742.
- Merrill JT, Tanaka Y, D’Cruz D, Vila-Rivera K, Siri D, Zeng X, Saxena A, Aringer M, D’Silva KM, Cheng L, Mohamed MF, Siovitz L, Bhatnagar S, Gaudreau MC, Doan TT, Friedman A. Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Patients With Systemic Lupus Erythematosus: A Phase 2 Randomized Controlled Trial. Arthritis Rheumatol. 2024 Oct;76(10):1518-1529.