[Anti-CD19 treatment: the new gold standard for IgG4-related diseases]

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated, inflammatory, fibrosing multiorgan disease. The B cells and plasma cells play a central role in the pathophysiology, which makes B cell-targeted treatment particularly interesting for the disease. Although glucocorticoids still represent the first line treatment, recurrence under dose reduction is frequent. Immunosuppressants, such as methotrexate, azathioprine, mycophenolate mofetil or rituximab (anti-CD20) are used but larger studies on proof of benefits are lacking so that no approved treatment options for the disease currently exist. Using CD19 as the therapeutic target addresses a broad spectrum of B cell differentiation including plasmablasts. The multicenter randomized placebo-controlled phase 3 study MITIGATE (n = 135) first investigated the anti-CD19 antibody inebilizumab in active IgG4-RD. The treatment significantly reduced the risk of recurrence (10% vs. 60% under placebo), the annual exacerbation rate and the necessity for renewed administration of glucocorticoids. Additionally, under inebilizumab there was a median reduction of the IgG4 serum level of around 50% and a persisting depletion of B cells during the study period of 52 weeks. Severe undesired events occurred more frequently with inebilizumab, particularly infections and lymphopenia but without treatment-associated cases of death. Following approval of inebilizumab by the U.S. Food and Drug Administration (FDA) for IgG4-RD in 2025, approval in Europe is also soon to be expected. The anti-CD19 targeted treatment with inebilizumab could therefore become the new approved gold standard; however, long-term data on remission maintenance and health economic issues, especially in comparison to off-label treatment such as rituximab remain the subject of further research. New approaches, such as CD19 chimeric antigen receptor (CAR) T cell treatment or bispecific T cell engagers could furthermore open up future treatment options.