FDA approval of the B-cell depleting monoclonal antibody inebilizumab-cdon (Uplizna) a year ago for immunoglobulin (Ig)G4-related disease (RD) has cemented B-cell depletion as current first-line therapy for most patients and may even be driving increased awareness of the underrecognized disease by various specialists.

There are reasons for optimism, moreover, that therapeutic options will grow in coming years given advancing research on treatments that inhibit B-cell activity rather than depleting B cells, experts told Medscape Medical News. Such treatments — one of which has phase 3 trial data on its way to publication — could potentially play a role in first-line management for some patients and as maintenance therapy for others with the chronic, immune-mediated fibroinflammatory condition.

“Since The New England Journal of Medicine paper [reporting findings from the MITIGATE trial] and the FDA approval of inebilizumab, I’ve seen a significant increase in awareness among community physicians who were not very familiar with IgG4-RD disease,” said Arezou Khosroshahi, MD, who established and leads an IgG4-RD clinic at Emory University School of Medicine, Atlanta. “I see more patients are being evaluated for IgG4-RD.”

IgG4-RD has “transitioned from a largely rare disease that we were empirically treating with immunosuppression, lots of steroid, and not as much evidence-based treatment,” Khosroshahi said, “to a disease for which we now have an evidence base showing that B-cell depletion really works.”

The evidence was bolstered late last year with post hoc analyses of MITIGATE trial data presented at the American College of Rheumatology (ACR) 2025 Annual Meeting. The analyses confirmed the treatment’s efficacy and safety across patient subgroups with differing baseline clinical characteristics, including disease duration and IgG4 serum levels, and with different organ involvement. Khosroshahi, professor of medicine at Emory, was a co-investigator of the MITIGATE trials and the post hoc analyses.

Indeed, said Matthew C. Baker, MD, MS, an expert in IgG4-RD at Stanford University School of Medicine, Palo Alto, California, while other methods of immunomodulation are currently being explored, “our best results have come from targeting B cells. That’s the main focus of the field right now.”

The Impact of Inebilizumab, Plus Outstanding Questions

Prior to the approval of inebilizumab, physicians and their patients had positive experiences overall with rituximab as a steroid-sparing medication and B-cell depleting agent, Baker and Khosroshahi said, but its efficacy had not been rigorously evaluated.

The international phase 3 double-blind, randomized, placebo-controlled MITIGATE trial was the first such trial involving patients with IgG4-RD. It demonstrated an 87% reduction in flare risk with inebilizumab and nearly fivefold greater likelihood of flare-free remission at 1 year compared with placebo.

Inebilizumab targets CD19+ B cells and, in doing so, casts a wider net than rituximab, which targets the CD20 protein found on B cells. “CD20 is expressed on the majority of lineages [of B cells] but not all of them, while CD19 is expressed on essentially all lineages of circulating B cells, except the plasma cells,” said Baker, assistant professor of medicine and associate division chief for immunology and rheumatology at Stanford.

“CD19 does get expression on plasmablasts,” he noted, “which are circulating antibody-producing cells that we think are generally expanded in patients with IgG4-RD.”

Inebilizumab has also benefitted from newer molecular engineering techniques: It is a fully humanized monoclonal antibody rather than a chimeric one, which lessens the risk for negative infusion reactions, and it is glycoengineered, which enhances its interaction with natural killer cells.

Theoretically, CD19-targeted B-cell depletion should keep patients in remission longer. But only time will tell, Baker and Khosroshahi said. In the MITIGATE trial, 135 adults received 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26, with outcomes measured at 1 year. A 3-year open-label extension study of inebilizumab treatment is currently underway.

“It’s difficult to predict [how long-lasting the treatment effects will be] because IgG4 is such a heterogeneous disease,” Khosroshahi said. “Some patients have a very high load of disease…and may require more frequent treatments for a couple of years before stopping. And some who have less organ involvement may respond to two doses and go for a couple of years without flaring.”

For now, Khosroshahi describes inebilizumab to her patients as “an upgraded version of rituximab.” Insurance approval for inebilizumab is still variable, making rituximab the fallback strategy in some cases. “But we’re definitely trying to make sure it becomes the standard of care,” she said. “And the sooner patients start it, the sooner they will be in remission with less damage to their organs and less damage from steroid toxicities.”

With time required for the patient’s consideration of treatment and for insurance approval, hepatitis and tuberculosis testing, vaccinations, and infusion scheduling, Khosroshahi usually still prescribes steroids as a bridge to B-cell depletion.

Some patients with only mild involvement, such as with the lacrimal or salivary glands, may not need B-cell depletion, Baker noted. “But for anything significant, any internal organ involvement, we generally go straight to B-cell depletion with or without steroids depending on severity,” he said.

The safety of B-cell depletion with inebilizumab continues to be assessed through a MITIGATE safety follow-up period of up to 730 days for all participants. During the treatment period of the MITIGATE trial, serious adverse events occurred in 12 of the patients receiving inebilizumab (18%) and six of those receiving placebo (9%). No serious adverse event occurred in more than one patient, and there were no deaths.

Adverse events that occurred in more than 10% of the inebilizumab recipients were COVID in 16 patients (24%), lymphopenia in 11 (16%), and urinary tract infection in eight (12%).

MITIGATE Post Hoc Analyses Confirm Broad Efficacy

One of the two post hoc subgroup analyses of MITIGATE trial data looked at disease duration (< 2 years and ≥ 2 years), whether IgG4 disease was newly diagnosed or recurrent, highest known IgG4 serum level, ACR-European Alliance of Associations for Rheumatology classification criteria score, CD20 B-cell count, and whether or not the patient had prior maintenance therapy.

For each subgroup, outcomes were similar — with similar hazard ratios for flare and remission rates in the treatment vs placebo groups — to those of the overall study population.

The other analysis considered baseline organ manifestations and defined subgroups by the organs most commonly involved (lymph nodes, pancreas, submandibular glands, lacrimal glands, kidney, bile ducts, and parotid glands), by involvement of organs with potentially urgent or severe manifestation (pancreas, kidney, bile ducts, aorta and large blood vessels, and orbits) and by organs characteristic of the fibrotic phenotype of IgG4-RD (retroperitoneum, mediastinum, mesentery, thyroid, and meninges).

Inebilizumab reduced the risk for flare relative to placebo in all organ subgroups, with hazard ratio values similar to those of the overall population, and with the greatest effect observed in patients with pancreatic, bile duct, and kidney involvement.

In the case of fibrotic organs, “we didn’t have the patient numbers to conclude there was a statistically significant difference [between treatment and placebo], but the trend was consistent and suggested [these patients] were responsive,” Khosroshahi said.

Broadly speaking, the breakdown of organ manifestation also paints a picture of “where patients are being seen, where they’re coming [to rheumatology] from,” said Alvin Wells, MD, PhD, a rheumatologist with the American Medical Group in Destin, Florida. “A lot of these patients are in the gastroenterologists’ offices and in the ENTs’ [offices].”

Wells spoke at a “year in review” session at the 2026 Rheumatology Winter Clinical Symposium in Maui, Hawaii, where the post hoc MITIGATE analyses were highlighted as among the most important papers of 2025 on systemic autoimmune diseases.

IgG4-RD only recently — in 2023 — received an International Classification of Diseases, 10th Revision code, approximately 20 years after it was first described in the literature. In 2024, John H. Stone, MD, of Harvard Medical School, Boston, and a lead author of MITIGATE trial, told Medscape Medical News that a reported estimated prevalence of about 5.3 persons per 100,000 was likely to be a three- to four-fold underestimate.

Research Explores B-Cell Inhibition

B-cell depletion, particularly long-term depletion, can have serious side effects — most notably, hypogammaglobulinemia and the risk for significant infection. “With [repeated] depletion for long enough, at least 5% of patients will become chronically hypergammaglobulinemic and about 5% will require immunoglobulin replacement therapy. And other patients will suffer from infections they probably otherwise wouldn’t have experienced,” Baker said. “In a perfect world, we wouldn’t have to deplete B cells over and over.”

Bruton tyrosine kinase inhibitors (BTKi), which are utilized in oncology for some B-cell driven malignancies, may be part of a next generation of nondepleting treatment options for IgG4-RD. The agents inhibit an important pathway in the activation and proliferation of B cells without meaningfully reducing B cell numbers.

In one of the two open-label phase 2 studies on BTK inhibition for IgG4-RD presented at the annual ACR meeting in 2025, 24 weeks of the oral BTKi zanubrutinib (80 mg twice daily) significantly reduced lacrimal and/or submandibular gland volume and metabolic activity on FDG-PET/MRI, as well as serum IgG4 concentrations.

Baker designed the 10-patient study as an investigator-initiated study to focus on patients who had active disease but were not receiving glucocorticoids or immunosuppressive therapy. This differs, he said, from the common study protocol in which patients receive steroids for several weeks, are randomly assigned to drug or placebo with steroids tapered off and then are monitored for flares.

Not only do “steroids have a lot of toxicity…but it’s hard to directly assess the activity of the [new] drug due to the confounding improvement from steroids. For this reason, patients must be followed until they flare,” Baker said. (He did not include patients with severe internal organ involvement, in whom the standard of care is to receive steroids.)

Treatment with zanubrutinib had “a pretty profound effect: a 45% reduction in lacrimal gland volume and a 30% reduction in submandibular (gland volume), and metabolic activity was almost fully suppressed,” said Baker, who presented the findings at ACR 2025. “It was a nice proof of concept that this mechanism has a real effect. In the future, at least for some patients, it could potentially be used without steroids.”

The other open-label phase 2 study, presented at ACR 2025 by Stone, had a more traditional design. Prednisone was tapered off during the first 4 weeks of a 52-week treatment period with the BTKi rilzabrutinib (or placebo), and disease activity was tracked with the IgG4-RD Responder Index.

The proportion of participants on rilzabrutinib monotherapy without a disease flare by the end of treatment was 19 of 27 (70%) and was similar in patients who had a history of treatment with rituximab and those who were rituximab-naive, according to the abstract.

“There was a nice signal for benefit,” Baker said. Based on these findings, including adverse events that were mostly mild, patients are currently being recruited for an international Sanofi-sponsored phase 3 randomized controlled trial of rilzabrutinib.

Further along the research process is the monoclonal antibody obexelimab, which targets CD19 and Fc gamma receptor IIb receptors to inhibit the activity of B cells. Positive topline results from a phase 3 trial of obexelimab for IgG4-RD — a statistically significant 56% reduction in the risk for flare over 52 weeks — were reported by Zenas BioPharma in January. Full data are expected to be presented soon, Baker said.

Obexelimab and the BTKi “are very promising mechanistically for IgG4-RD [given their] modulation of the immune system,” Khosroshahi said. “I don’t think any of them will be able to beat B-cell depletion, but their usage would be different.”

For instance, “for a patient who doesn’t have significant organ threatening disease, I’d rather use a BTK inhibitor or CD19 inhibitor rather than depleting all their B cells,” she said. “Or as we do with other autoimmune diseases, [for those with significant IgG4-RD] we could use a combination — inebilizumab to induce remission, and then a B-cell inhibitor for maintenance.”

Treatment Targets Other Than B Cells

While the focus is on B cells, other avenues are still being explored for treatment of IgG4-RD, Baker said. At Stanford, he is currently recruiting patients, for instance, for an investigator-initiated, open-label, phase 2 study of efgartigimod, a neonatal Fc receptor (FcRn) blocker that is administered subcutaneously.

Inhibition of FcRn prevents the recycling of IgG antibodies and promotes their degradation, Baker said. Efgartigimod is already FDA approved for treatment of generalized myasthenia gravis and chronic inflammatory demyelinating polyneuropathy, and supporting studies showed a 60%-80% reduction in circulating IgG levels by 4-6 weeks, he said.

“We’re interested in understanding if we’ll see benefit in IgG4-RD by reducing immunoglobulins without touching the B cells or any other immune cell directly,” he said.

Research on abatacept, a T-cell co-stimulation inhibitor approved for rheumatoid arthritis and other rheumatic diseases, showed a “modest effect” for IgG4-RD, but the findings “were not enough to push it along further,” Baker noted.

Khosroshahi disclosed being an adviser/consultant with Amgen, the manufacturer of inebilizumab. Baker disclosed being an adviser/consultant with Amgen, Zenas BioPharma, Sanofi, and Argenx. Wells reported having financial relationships with Amgen and Sanofi, among other pharmaceutical companies. Stone reported having financial relationships with Amgen, Argenx, Sanofi, and Zenas.