Rituximab Maintenance Therapy Reduces Rate of Relapse of Pancreaticobiliary Immunoglobulin G4-related Disease.

BACKGROUND & AIMS: IgG4-related disease (IgG4-RD), a multi-organ fibroinflammatory syndrome, typically responds to steroids. However, some cases are steroid resistant, and pancreaticobiliary IgG4-RD commonly relapses after steroid withdrawal. Rituximab induces remission of IgG4-RD, but the need for and safety of maintenance rituximab treatment are unknown. We compared outcomes of patients with pancreaticobiliary IgG4-RD treated with or without maintenance rituximab therapy. METHODS: We performed a retrospective study of patients with pancreaticobiliary IgG4-RD treated with rituximab at the Mayo Clinic in Rochester, Minnesota, from January 2005 through December 2015. The cohort was divided into patients who received only rituximab induction therapy (group 1, n = 14) and patients who received rituximab induction followed by maintenance therapy (group 2, n = 29). We collected data on recurrence of IgG4-RD symptoms and findings, as well as information on evaluations, treatment, and adverse events. RESULTS: Median follow-up times were similar between group 1 (34 mo) and group 2 (27 mo) (P = .99). Thirty-seven patients (86%) were in steroid-free remission 6 months after rituximab initiation. A higher proportion of patients in group 1 had disease relapse (3-year event rate, 45%) than in group 2 (3-year event rate, 11%) (P = .034). Younger age, higher IgG4 responder index score after induction therapy, and increased serum levels of alkaline phosphatase at baseline or after rituximab induction were associated with relapse. Infections developed in 6 of 43 patients, all in group 2 (P = .067 vs group 1); all but 1 occurred during maintenance therapy. CONCLUSIONS: In a retrospective study of patients with pancreaticobiliary IgG4-RD, we found rituximab maintenance therapy prolongs remission. Relapses are uncommon among patients receiving maintenance therapy, but maintenance therapy may increase risk of infection. Patients with factors that predict relapse could be candidates for rituximab maintenance therapy.

High Detection Rates of Pancreatic Cancer Across Stages by Plasma Assay of Novel Methylated DNA Markers and CA19-9.

PURPOSE: We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case-control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC. EXPERIMENTAL DESIGN: Thirteen MDMs (GRIN2D, CD1D, ZNF781, FER1L4, RYR2, CLEC11A, AK055957, LRRC4, GH05J042948, HOXA1, PRKCB, SHISA9, and NTRK3) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated. RESULTS: The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89-0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87-0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98-1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76-0.92), CA19-9 alone was 0.87 (0.79-0.94), and combined MDM-CA19-9 panel was 0.90 (0.84-0.97) significantly better compared with either MDMs alone or CA19-9 alone (P = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%-99%) for stage I disease and 82% (68%-92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86-0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84-0.93) versus 0.97 (0.94-0.99) for the combined MDM-CA19-9 panel (P ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%-98%), with an observed specificity of 92% at the preset specificity of 97.5%. CONCLUSIONS: Plasma MDMs in combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.