High affinity anti‐BSEP antibodies after liver transplantation for PFIC‐2 – Successful treatment with immunoadsorption and B‐cell depletion

Abstract

PFIC due to BSEP mutations (PFIC type 2) often necessitates OLT. It has recently been recognized that some PFIC-2 patients develop phenotypic disease recurrence post-OLT due to the appearance of anti-BSEP antibodies. Here, we describe a boy who became cholestatic four yr after OLT during modification of immunosuppression. Canalicular antibody deposits were detected in biopsies of the transplant and antibodies specifically reacting with BSEP were identified at high titers in his serum. These antibodies bound extracellular epitopes of BSEP and inhibited BS transport and were assumed to cause disease recurrence. Consequently, anti-BSEP antibody depletion was pursued by IA and B-cell depletion by anti-CD20 antibodies (rituximab) along with a switch of immunosuppression. This treatment resulted in prolonged relief of symptoms. Depletion of pathogenic anti-BSEP antibodies causing AIBD after OLT in PFIC-2 patients should be considered as a central therapeutic goal.

Alloimmunity and Cholestasis After Liver Transplantation in Children With Progressive Familial Intrahepatic Cholestasis

“…PFIC-2 is an inherited cholestatic liver disorder in which several identified genetic mutations lead to dysfunction or complete absence of BSEP (16). Our 3 patients developed refractory recurrence of low-g-GT cholestasis and graft failure due to anti-BSEP antibodies after LT. Over the last few years, several patients have been reported with proven antibodies against BSEP and recurrence of cholestatic liver disease following LT for PFIC-2 mimicking the original disease (9)(10)(11)(12)(13). The reason for this alloimmune process seems to be multifactorial.…”

“…The occurrence of antibody formation against BSEP in the transplanted liver in patients with PFIC-2 was first reported in 2009 (1,10). Since then, more than 20 patients have been reported with recurrent low g-GT cholestasis following LT for PFIC-2 mimicking the original disease (9)(10)(11)(12)(13). In most of these cases, intensifying the immunosuppression led to normalization of graft function (13).…”

Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis

“…Immunofluorescence (IF) or immunohistochemistry (IHC) staining of patient liver tissues is commonly used in clinical practice to identify the presence of these antibodies ( Kubitz et al, 2015 )Anti-BSEP antibody-associated cholestasis severity correlates with the level of anti-BSEP antibodies in the body. Reducing this antibody titer can improve cholestatic hepatitis within days by removing the antibody from plasma using immunosorbent therapy ( Kubitz et al, 2016 ). Cetuximab has also been studied for its potential therapeutic effect on this condition by binding to plasma cells and BSEP antibodies.…”

Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis

“… 50 This can be treated with B-cell–depleting antibody therapy such as rituximab, intravenous immunoglobulin, plasmapheresis, and steroids. 51 , 52 …”