Design: Phase III, multicentre, randomised, double-blind, placebo-controlled trial
Population: 222 adults with moderate-to-severe pemphigus (190 pemphigus vulgaris)
Primary outcome: Complete remission on ≤10 mg prednisone for ≥8 weeks by week 30
Effect: 35.5% vs 30.3%, OR 1.19 (0.60 to 2.41), p = 0.60

ADDRESS was a global phase III double-blind trial that randomised 222 adults with newly diagnosed or relapsing moderate-to-severe pemphigus, 190 with pemphigus vulgaris, 2:1 to subcutaneous efgartigimod or placebo. Efgartigimod blocks the neonatal Fc receptor and lowers circulating IgG, including pathogenic autoantibodies. Everyone started prednisone at 0.5 mg/kg a day.

The primary outcome, complete remission on 10 mg or less of prednisone for at least eight weeks by week 30 in pemphigus vulgaris, was reached by 35.5% with efgartigimod and 30.3% with placebo (OR 1.19, 95% CI 0.60 to 2.41, p = 0.60). Total prednisone use was similar. Efgartigimod lowered total IgG and anti-desmoglein 1 and 3 antibodies quickly, but disease activity scores did not improve. Adverse events were more frequent with efgartigimod (89.1% vs 76.0%), while serious events were similar (12.2% vs 13.3%).

The trial is a clear negative. Lowering antibody levels was not enough to improve clinical outcomes over steroids alone, which argues against using FcRn blockers in pemphigus outside trials. Steroid-sparing treatment should continue to follow current guidance; this trial gives no reason to change it.

Do not use efgartigimod for pemphigus outside a clinical trial on this evidence.
Continue to follow current guidance on steroid-sparing therapy for moderate-to-severe pemphigus.
Do not treat falling desmoglein antibody levels alone as proof of clinical response.
Judge response by lesion healing and disease activity scores, not antibody titres alone.
Discuss the result with patients who ask about newer antibody-lowering drugs.

Why it matters

Lowering the pathogenic antibody did not translate into healing, which challenges the logic of antibody-depletion alone in pemphigus.

The statistics, in plain English

An odds ratio of 1.19 with an interval from 0.60 to 2.41 crosses 1.0, so no benefit was shown; the small numerical difference could easily be chance. The fall in antibodies is a surrogate marker, and this trial shows that the surrogate moved while the clinical outcome did not.