Cholestatic Liver Disease after Rituximab and Adalimumab and the Possible Role of Cross-Reacting Antibodies to Fab 2 Fragments

Joerg Latus,Martin Kimmel,Reinhild Klein,Peter Fritz,Matthias Schwab,Ina Koetter,Niko Braun,M Dominik Alscher,Sophia N Karagiannis

doi:10.1371/journal.pone.0078856

Abstract

BackgroundMillions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group.MethodsThree sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin.ResultsViral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients’ sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected.ConclusionThis is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug clearance in patients on Tmab therapy.

Highlights

Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases
Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily expressed on the surface of B cells
One patient with a remarkably severe course of Granulomatosis and Polyangiitis (GPA) with different second and third line therapies, 5 patients who were previously treated with intravenous immune globulin due to different diseases and 9 healthy blood donors served as controls

Summary

Introduction

Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. The monoclonal anti CD20 antibody Rituximab is widely used. Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily expressed on the surface of B cells. There are only two published cases suggesting significant liver toxicity after rituximab infusion [2,3]. There are only a few case reports of fatal infections after treatment with rituximab in the current literature [4,5,6,7]. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophilcytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group

Methods

Results

Conclusion