Krusche Martin
Sektion für Rheumatologie und Entzündliche Systemerkrankungen in der III. Medizin, Universitätsklinikum Hamburg-Eppendorf (UKE), Martinistr. 52, 20246, Hamburg, Deutschland.
Z Rheumatol. 2025 Sep;84(7):552-556. doi: 10.1007/s00393-025-01682-4. Epub 2025 Jul 31.
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.
免疫球蛋白G4相关疾病（IgG4-RD）是一种免疫介导的、炎症性的、纤维化的多器官疾病。B细胞和浆细胞在其病理生理学中起核心作用，这使得针对B细胞的治疗对该疾病特别有意义。尽管糖皮质激素仍然是一线治疗药物，但在减药过程中疾病复发很常见。免疫抑制剂，如甲氨蝶呤、硫唑嘌呤、霉酚酸酯或利妥昔单抗（抗CD20）也被使用，但缺乏关于其益处的大型研究证据，因此目前尚无该疾病的获批治疗方案。以CD19作为治疗靶点可针对包括浆母细胞在内的广泛B细胞分化阶段。多中心随机安慰剂对照3期研究MITIGATE（n = 135）首次对活性IgG4-RD患者研究了抗CD19抗体依内布利珠单抗。该治疗显著降低了复发风险（10%对比安慰剂组的60%）、年加重率以及再次使用糖皮质激素的必要性。此外，在依内布利珠单抗治疗期间，IgG4血清水平中位数降低约50%，并且在52周的研究期内B细胞持续耗竭。依内布利珠单抗导致的严重不良事件更频繁发生，尤其是感染和淋巴细胞减少，但没有与治疗相关的死亡病例。2025年美国食品药品监督管理局（FDA）批准依内布利珠单抗用于治疗IgG4-RD后，预计欧洲也将很快批准。因此，依内布利珠单抗的抗CD19靶向治疗可能成为新的获批金标准；然而，关于缓解维持的长期数据以及健康经济学问题，尤其是与利妥昔单抗等非标签治疗相比，仍有待进一步研究。新的方法，如CD19嵌合抗原受体（CAR）T细胞治疗或双特异性T细胞衔接器，可能会开辟未来的治疗选择。
