A recent study published in the Rheumatic & Musculoskeletal Diseases Open reported that combination therapy with nipocalimab and certolizumab pegol did not significantly improve clinical outcomes compared with certolizumab monotherapy in patients with active rheumatoid arthritis who had previously received advanced therapies.
Nipocalimab is a fully human monoclonal antibody that targets the neonatal Fc receptor (FcRn). FcRn plays an important role in maintaining circulating immunoglobulin G (IgG) levels by protecting IgG from intracellular degradation and enabling its recycling back into the circulation. Nipocalimab binds selectively to FcRn with high affinity and blocks the interaction between endogenous IgG and FcRn. This mechanism prevents IgG recycling and leads to enhanced degradation of circulating IgG, resulting in reduced serum levels of IgG, including pathogenic autoantibodies. Nipocalimab is currently approved for the treatment of generalized Myasthenia Gravis and is being evaluated for several conditions mediated by IgG autoantibodies or alloantibodies.
Certolizumab pegol is a PEGylated fragment antigen-binding (Fab) anti-tumour necrosis factor agent approved for the treatment of adults with moderate to severe rheumatoid arthritis. By neutralising tumor necrosis factor Alpha, a key pro inflammatory cytokine involved in the pathogenesis of RA, certolizumab suppresses myeloid immune activation, reduces synovial inflammation, and helps limit structural joint damage. Because certolizumab lacks an Fc region, its circulating levels are not expected to be reduced by concomitant treatment with an anti-FcRn agent such as nipocalimab. This contrasts with IgG based monoclonal antibodies that contain an Fc domain.
The phase 2a DAISY RA study evaluated the efficacy, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of the nipocalimab and certolizumab combination in patients with active RA despite prior treatment with at least one advanced therapy. A total of 103 participants were randomised in a 3:2 ratio to receive either combination therapy consisting of intravenous nipocalimab at 30 mg/kg together with subcutaneous certolizumab administered at 400 mg at weeks 0, 2, and 4 followed by 200 mg every two weeks, or certolizumab monotherapy. Treatment was administered from week 0 through week 24.
The primary endpoint was the change from baseline in the Disease Activity Score in 28 joints using C reactive protein (DAS28 CRP) at week 12. The primary outcome was comparable between the two treatment groups. The least squares mean change in DAS28 CRP at week 12 was −1.92 with combination therapy (90% CI −2.48 to −1.36) and −1.86 with certolizumab monotherapy (90% CI −2.44 to −1.28). The difference between groups was not statistically significant (p = 0.822).
Secondary endpoints showed similar trends across the two groups. Numerically higher proportions of participants in the combination therapy arm achieved ACR50 response as well as DAS28 CRP targets of less than 2.6 and less than or equal to 3.2 at week 12, although these differences did not translate into a clinically meaningful advantage.
From a safety perspective, serious adverse events were reported in 11.3% of participants receiving combination therapy compared with 2.4% in the monotherapy group. Pharmacokinetic analyses indicated that nipocalimab demonstrated nonlinear pharmacokinetics when used with certolizumab, characterised by accelerated clearance. Pharmacodynamic assessments showed substantial but reversible reductions in circulating IgG levels, including anticitrullinated protein antibody (ACPA) IgG.
Despite the significant reductions in total IgG and ACPA levels, the combination regimen did not result in improved clinical efficacy compared with certolizumab alone. These findings suggest limited additive benefit of FcRn blockade with nipocalimab when combined with TNF inhibition in patients with active rheumatoid arthritis who have previously received advanced therapies.
The investigators noted that the direct pathogenic role of ACPA in rheumatoid arthritis remains complex and incompletely understood. The lack of improved clinical outcomes despite marked reductions in ACPA IgG levels suggests that additional immunological pathways beyond circulating IgG autoantibodies may contribute to disease activity. Further research may therefore be required to clarify the role of FcRn mediated IgG regulation and to identify patient subgroups that may benefit from FcRn targeted therapies.
Reference
Taylor PC, Schett G, Huizinga TWJ, Ibrahim F, Zhou B, Huang S, Gambale J, Wang Q, Liva SG, Leu JH, Hubbard JJ, Leonardo S, Panchakshari RA, Loza MJ, Fei K. Nipocalimab and certolizumab combination therapy in participants with active rheumatoid arthritis despite prior treatment with advanced therapies: results from the phase 2a DAISY-RA study. RMD Open. 2026 Mar 4;12(1):e006464.