Novel and traditional B-cell depleting agents for IgG4-related disease: a critical view

When one reads the lion-hearted wordings about the potential role of CD19-directed B cell depletion in autoimmune conditions that talk about developmental clocks that are reset ‘to a point that curtails the extent of emerging self-reactivity’ [1], one is seriously inclined to replace ‘England’ with ‘CD19-directed therapy’, as a referral to the 1978 song ‘Oh England My Lionheart’ by Kate Bush, and sing it out loud. Even more enthusiasm is spread when one awakes to the results of the recently published phase III MITIGATE [inebilizuMab effIcacy and safeTy in IGg4 relATEd disease (NCT04540497)] trial that evaluated the efficacy and safety of the anti-CD19 antibody inebilizumab for the treatment of immunoglobulin G4–related disease (IgG4-RD). Designed as a phase III, multicentre, double-blind, placebo-controlled trial, the MITIGATE trial randomized 135 patients with active IgG4-RD in a 1:1 ratio to receive either inebilizumab or placebo at 80 sites in 22 countries. Inebilizumab (at a dose of 300 mg) or placebo was administered intravenously on days 1 and 15 and at week 26 during the 52-week trial period, while glucocorticoids (GCs), which the enrolled subjects were taking at the time of trial entry for a recent disease flare, had to be tapered to discontinuation at week 8. The results sparkle in a promising way: at week 52, inebilizumab was found to reduce flare risk {10% versus 60%; hazard ratio [HR] 0.13 [95% confidence interval (CI) 0.06–0.28], P < .001} and treatment-free and flare-free complete remission was more frequently achieved in the inebilizumab group versus placebo [odds ratio (OR) 4.68 (95% CI 2.21–9.91), P < .001]. Serious adverse events occurred in 18% of the patients in the inebilizumab group and in 9% of those in the placebo group. Moreover, the authors reported a total mean GC use per participant of 118.3 mg in the inebilizumab group versus 1384.5 mg in the placebo group, and complete GC withdrawal was more often possible in the treatment group (90% versus 37%). As measured by peripheral CD20+ B cell levels, inebilizumab induced sustained B cell depletion beginning at week 2. A significant decrease in serum IgG4 levels was also detected during the treatment period