CO:01:1 | Efficacy and safety of rituximab across the four phenotypes of IgG4-related disease: a European multi-center cohort study of 115 patients

Marco Lanzillotta¹, Jens Vikse², Elisabetta Goni³, Veronica Batani¹, Jasmin Mahajne¹, Lorenzo Dagna¹, Emanuel Della Torre¹. | ¹Unit of Immunology, Rheumatology, Allergy, and Rare Disease, IRCCS Ospedale San Raffaele, Milano, Italy; ²Department of Rheumatology, Stavanger University Hospital, Norway; ³Department of Medicine II, University Hospital, Ludwig Maximilian University, Munich, Germany

Abstract

Background. IgG4-related disease (IgG4-RD) is a rare, immune-mediated fibroinflammatory disorder that affects various organs. Four distinct clinical phenotypes have been described based on organ involvement, yet it is unknown whether treatment response to B-cell depletion varies across them. This study aimed to evaluate the efficacy and safety of rituximab (RTX) across the four IgG4-RD phenotypes in a large real-world European cohort.

Materials and Methods We retrospectively analyzed prospectively collected data from adult patients with IgG4-RD treated with RTX at three tertiary centers in Europe—Oslo University Hospital (Norway), San Raffaele Scientific Institute (Milan, Italy), and LMU University Hospital (Munich, Germany). Patients were categorized into four phenotypes: pancreato-hepato-biliary, retroperitoneum and aorta, head and neck-limited, and Mikulicz’ and systemic disease. The primary endpoint at 6 months was a composite of treatment response (gretaer than 2-points decrease in responder index [RI]), absence of flare, and low-dose or no glucocorticoid (lower than 7.5 mg). Secondary endpoints included flare, remission, GC discontinuation, and safety events at 6 and 12 months.

Results. We included 115 patients: 33 (28.7%) had pancreato-hepato-biliary disease, 22 (19.1%) retroperitoneal and aortic disease, 19 (16.5%) head and neck-limited disease, and 41 (35.7%) Mikulicz’ and systemic disease. All phenotypes showed comparable response to RTX, with 80 patients (70%) achieving the primary endpoint. However, the retroperitoneum and aorta phenotype had the lowest remission rate at 6 months (4.5% vs 18.2–36.6%, p=0.025), and the head and neck-limited phenotype had the highest flare rate at 12 months (38.9% vs 4.8–25.0%, p=0.006) (Figure 1). Fulfillment of the 2019 ACR/EULAR classification criteria was lower in these two phenotypes. Higher baseline RI score and criteria fulfillment predicted treatment response. Safety profiles were similar across phenotypes. Infusion reactions were most frequent in the head and neck-limited group (31.6%, p=0.021), and infection rates were not significantly different.

Conclusions. In this multicenter European study, RTX was effective across all IgG4-RD phenotypes, though patients with retroperitoneum and aorta or head and neck-limited disease appeared less treatment responsive, including lower remission and higher flare rates. These phenotypes also showed lower rates of classification criteria fulfillment, suggesting potential under-representation in clinical trials. Our findings emphasize the need for phenotype-oriented treatment strategies and encourage inclusive trial designs in IgG4-RD.

Keywords

• IgG4-RD
• Rituximab
• Phenotypes