Highlight
– In the phase 2 DAHLIAS trial, nipocalimab 15 mg/kg IV every 2 weeks for 22 weeks produced a statistically significant reduction in ClinESSDAI at week 24 versus placebo (LS mean difference -2.65; 90% CI -4.03 to -1.28; p=0.0018).
– The lower 5 mg/kg dose did not differ from placebo. Safety and serious adverse event rates were broadly similar across arms.
– Treatment reduced circulating IgG autoantibodies, supporting a pathogenic role for IgG in a biologically selected (anti‑Ro positive) Sjögren’s population.
Background and disease burden
Sjögren’s disease (primary Sjögren’s syndrome) is a systemic autoimmune disease characterised by lymphocytic infiltration of exocrine glands leading to mucosal dryness (xerostomia and keratoconjunctivitis sicca), and commonly associated with disabling systemic features such as fatigue, arthralgia, myalgia and, in some patients, organ‑threatening extraglandular involvement. Disease manifestations are heterogeneous and often chronic, and many patients have circulating autoantibodies, most frequently anti‑Ro/SSA and anti‑La/SSB IgG. Currently there are no licensed disease‑modifying therapies that reliably alter disease course; management remains focused on symptomatic relief and off‑label use of immunomodulators for systemic manifestations. New targeted approaches that act on mechanistic drivers of disease are therefore a high unmet need.
Study design (DAHLIAS)
DAHLIAS was a multicentre, randomised, double‑blind, placebo‑controlled, phase 2 trial designed to evaluate nipocalimab (an anti‑neonatal Fc receptor [FcRn] monoclonal antibody) in adult patients with moderate‑to‑severe, active Sjögren’s disease. Key inclusion criteria included a Clinical European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ClinESSDAI) of ≥6 and seropositivity for anti‑Ro IgG autoantibodies. The trial enrolled 163 participants at 69 centres across Europe, Asia, and the USA between September 2021 and April 2023.
Participants were centrally randomised 1:1:1 using an Interactive Web Response System to receive intravenous nipocalimab 5 mg/kg, nipocalimab 15 mg/kg, or placebo administered every 2 weeks for 22 weeks (identical administration schedules and masked labels). The primary endpoint was change from baseline in ClinESSDAI score at week 24. The primary and other efficacy and safety analyses included all randomised participants who received at least one dose of study intervention, analysed using a mixed model for repeated measures (MMRM). Data collected after discontinuation were considered missing for the primary endpoint analysis. DAHLIAS was registered with EudraCT (2021‑000665‑32) and ClinicalTrials.gov (NCT04968912).
Key findings
Population
163 participants were randomised and treated (nipocalimab 5 mg/kg n=53; nipocalimab 15 mg/kg n=54; placebo n=56). Mean age was 48.1 years (SD 12.1); 93% were female. All participants were anti‑Ro IgG positive by protocol.
Primary efficacy outcome
The nipocalimab 15 mg/kg arm demonstrated a statistically significant reduction in ClinESSDAI score at week 24 compared with placebo (least squares mean difference -2.65; 90% CI -4.03 to -1.28; p=0.0018). The 5 mg/kg dose did not separate from placebo (LS mean difference -0.34; 90% CI -1.71 to 1.03; p=0.68).
These results indicate a dose‑dependent treatment effect, with the higher dose producing an average reduction in clinician‑assessed systemic disease activity relative to placebo over 24 weeks.
Autoantibody and pharmacodynamic effects
Nipocalimab’s known mechanism—blocking FcRn—increases IgG catabolism and lowers circulating IgG concentrations, including pathogenic autoantibodies. DAHLIAS reported reductions in IgG autoantibody levels during treatment, consistent with the expected pharmacodynamic action. The observed decline in anti‑Ro IgG supports a mechanistic link between humoral autoimmunity and ClinESSDAI‑assessed disease activity in the selected seropositive population.
Safety
Overall safety was comparable between nipocalimab (both doses) and placebo. Rates of adverse events and serious adverse events were generally similar across groups. No new safety signals emerged in this phase 2 cohort. The tolerability profile supports further clinical development, although larger and longer studies are required to better characterise uncommon or delayed risks associated with sustained IgG lowering.
Statistical and clinical interpretation
The statistical significance for the 15 mg/kg dose (p=0.0018) and the reported LS mean difference (-2.65) indicate a robust trial signal. The trial reported 90% confidence intervals rather than the more conventional 95% intervals; readers should note this when interpreting precision. The clinical meaningfulness of the observed change depends on context: ClinESSDAI quantifies systemic disease activity across organ domains, and the absolute magnitude of benefit should be interpreted against baseline disease severity and patient‑level outcomes (including symptom scales). DAHLIAS demonstrates a biologically plausible, dose‑responsive reduction in objective disease activity in an enriched anti‑Ro positive cohort.
Expert commentary and interpretation
Mechanistic rationale: FcRn blockade targets FcRn‑mediated IgG recycling, lowering total IgG and autoantibody titres without directly depleting B cells. This mechanism can produce relatively rapid reductions in pathogenic IgG species and has theoretical advantages where IgG autoantibodies are central to pathogenesis.
Clinical implications: For clinicians and clinical researchers, DAHLIAS provides proof‑of‑concept that targeting IgG homeostasis can reduce systemic disease activity in seropositive Sjögren’s disease. The trial’s inclusion of anti‑Ro positive participants enriched for autoantibody‑driven disease, which likely enhanced the capacity to detect an effect. Whether the benefit extends to seronegative patients is unknown.
Comparison with other approaches: Prior B‑cell directed strategies (for example, rituximab) have produced mixed results in Sjögren’s, with some patients and subgroups benefiting while larger trials struggled to meet primary endpoints. FcRn blockade is mechanistically complementary to B‑cell therapies and may be particularly relevant when pathogenic IgG mediators are established.
Limitations and unanswered questions
- Duration and durability: DAHLIAS reports outcomes through 24 weeks. Long‑term efficacy, durability after treatment cessation, and optimal maintenance strategies remain to be defined.
- Symptom outcomes: The primary endpoint was ClinESSDAI, an objective clinician‑rated disease activity index. Patient‑reported symptoms such as dryness, fatigue and pain are central to patient experience and may not correlate directly with ClinESSDAI changes; full patient‑reported outcome data should be examined.
- Generalizability: The trial enrolled anti‑Ro seropositive patients with ClinESSDAI ≥6; applicability to seronegative or milder disease populations is uncertain.
- Statistical considerations: The use of 90% confidence intervals is less conservative; subsequent larger trials should prespecify conventional two‑sided 95% CIs, hierarchical testing for multiplicity, and clinically anchored responder definitions.
Future directions
DAHLIAS supports advancing nipocalimab to larger phase 3 studies that should: recruit broader patient populations (including seronegative cohorts or stratified analyses), evaluate longer treatment durations and follow‑up for durability, include prespecified patient‑reported outcomes and health‑related quality of life measures, and power for clinically meaningful responder thresholds. Biomarker analyses (autoantibody kinetics, IgG subclass changes, tissue biomarkers) may help identify responders and refine a precision‑medicine approach.
Conclusion
DAHLIAS provides compelling phase 2 evidence that FcRn blockade with nipocalimab 15 mg/kg IV every 2 weeks reduces clinician‑assessed systemic disease activity in anti‑Ro seropositive patients with moderate‑to‑severe Sjögren’s disease, with a safety profile comparable to placebo over 24 weeks. The observed reductions in IgG autoantibodies bolster the biological rationale that pathogenic IgG contributes to disease activity in a subset of patients. These data justify phase 3 evaluation to establish clinical benefit across broader endpoints, longer follow‑up, and in diverse patient subgroups.
Funding and trial registration
DAHLIAS was funded by Johnson & Johnson. Trial registrations: EudraCT 2021‑000665‑32; ClinicalTrials.gov NCT04968912.
References
1. Noaiseh G, Sivils KL, Campbell K, et al. Efficacy and safety of nipocalimab in patients with moderate‑to‑severe Sjögren’s disease (DAHLIAS): a randomised, phase 2, placebo‑controlled, double‑blind trial. Lancet. 2025 Nov 22;406(10518):2435‑2448. doi:10.1016/S0140‑6736(25)01430‑8. PMID: 41284548.
2. DAHLIAS trial registration: ClinicalTrials.gov NCT04968912; EudraCT 2021‑000665‑32.
Author note
This article synthesises and interprets the DAHLIAS phase 2 results for a clinical and scientific audience. The primary source for data is the published Lancet report (Noaiseh et al.). Clinicians should await confirmatory phase 3 data before changing standard clinical practice.
