Cholestatic liver disease after rituximab and adalimumab and the possible role of cross-reacting antibodies to Fab 2 fragments.
BACKGROUND
Millions 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.


METHODS
Three 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.


RESULTS
Viral 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.


CONCLUSIONS
This 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.
Department of Internal Medicine, Division of Nephrology, Robert-Bosch Hospital Stuttgart, Germany.
Joerg
J
Latus
Reinhild
R
Klein
Ina
I
Koetter
Matthias
M
Schwab
Peter
P
Fritz
Martin
M
Kimmel
M Dominik
MD
Alscher
Niko
N
Braun
D000208:Acute Disease; D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D003429:Cross Reactions; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D000069283:Rituximab; D020293:Vasculitis, Central Nervous System / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
D000893:Anti-Inflammatory Agents; D019268:Antibodies, Antineutrophil Cytoplasmic; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D007140:Immunoglobulin Fab Fragments; D007155:Immunologic Factors; D000069283:Rituximab; D000068879:Adalimumab