IgG4-RD in 3 Talks: Shorter Steroids, Earlier B-Cell Therapy Save

IgG4-related disease now has two phase 3 trials and its first dedicated treatment guidelines. Glucocorticoids remain the weak point.

IgG4-related disease is a fibroinflammatory condition that mostly affects men, usually diagnosed between 50 and 70. Glucocorticoids induce remission in more than 90% of patients. The trouble starts after the taper. A Monday session at ACR Convergence 2026, moderated by Matthew Baker and Arezou Khosroshahi, followed that problem across three talks. The IgG4ward! Foundation guidelines came out in The Lancet Rheumatology the same morning.

Emma Culver (Oxford) started with the cost. Relapse after the taper reached 56% at one year and 90% at three years in her cohorts. In a 2025 analysis, 74.5% of patients on a mean of 5 mg/day or more had a steroid-related adverse event, infection in 31%. Emanuel Della Torre (Milan) linked chronic steroid exposure to morbidity in his unpublished cohort.

The guidelines turn this into limits. Written by 62 investigators from 15 countries, they reached more than 80% agreement on 22 of 28 statements. Prednisone should start at no more than 30 to 40 mg/day, and induction with steroids alone should not pass 3 months. Steroid-sparing therapy is recommended at induction for most patients, with B-cell agents favoured over conventional immunosuppressants. Maintenance is selective: on-demand retreatment for many, fixed dosing for frequent relapses or critical organs. Vaccines, both zoster doses included, go before B-cell depletion. Most statements still rest on low-level evidence.

The preference for B-cell therapy rests on two phase 3 trials. Inebilizumab, a CD19 depleter, cut flare risk by 87% in MITIGATE (n=135). Obexelimab, which inhibits B cells through CD19 and FcγRIIb without depleting them, cut it by 56% in INDIGO (n=194). No head-to-head trial exists. The guidelines suggest depletion may hold remission better, while inhibition can be paused for vaccines and surgery.

The newer question is whether an oral drug can do the same job. Bruton tyrosine kinase sits downstream of the B-cell receptor and is also expressed on macrophages and eosinophils. In a phase 2a trial of rilzabrutinib (n=27), prednisone was tapered off over 2 to 4 weeks, and 19 of 27 patients (70%) were flare free at week 52 without steroids or immunosuppressants. Prior rituximab made little difference: 11 of 15 previously treated patients stayed flare free. The IgG4-RD Responder Index fell by a mean of 11 points. Diarrhoea, COVID-19 and dizziness were the most common adverse events. The phase 3 RILIEF trial is recruiting.

Zanubrutinib went further and skipped steroid induction. Baker and colleagues treated 10 patients with lacrimal and submandibular disease with 80 mg twice daily for 24 weeks. Lacrimal gland volume fell by 47% and submandibular volume by 30%. The Responder Index improved by 6 points and total lesion glycolysis on PET dropped. Serum IgG4 fell by 417 mg/dL, short of significance (p=0.08). Tobias Lanz (Stanford) used the trial samples to look at mechanism. Plasmablasts fell, and so did CD4+ cytotoxic T cells and Th2 cells, which fits a B and T cell loop behind the fibrosis. Serum IgE rose as IgG4 fell. His unpublished single-cell data show many IgG4+ memory B cells switching to IgE inside a type 2 memory cluster. Both BTK trials are small and open-label, and neither has a placebo arm.

Della Torre also revisited cancer. A 2022 meta-analysis of 10 studies gave a standardized incidence ratio of 2.57 (95% CI 1.72-3.84), with about 70% of cancers found within 36 months of diagnosis. A 2026 cohort from Michelson and colleagues in Annals of the Rheumatic Diseases found 0.81 (0.61-1.23) and pointed to detection and immortal time bias. Malignant mimics still need to be excluded before the diagnosis. Full-body imaging at diagnosis is his suggestion for now.

The direction is set. Steroids become a short bridge, and B-cell therapy starts earlier when the bile ducts, pancreas or kidneys are involved. Until a comparative trial exists, the choice between depleting and inhibiting will rest on organ involvement and comorbidity. An oral option would change that choice for many patients. The next data to watch are the RILIEF results and IgE in patients on long-term BTK inhibitors.