Rituximab as therapy for the recurrence of bile salt export pump deficiency after liver transplantation

Abstract

Progressive familial intrahepatic cholestasis type 2 (PFIC2) results from recessive mutations in the adenosine triphosphatebinding cassette B11 gene, which encodes for bile salt export pump (BSEP). Liver transplantation (LT) is offered to PFIC2 patients with end-stage liver disease. Reports have described recurrent cholestasis in PFIC2 patients after transplantation, and this has been associated with immunoglobulin G antibodies to BSEP. High-titer anti-BSEP antibodies appear to correlate with episodes of cholestatic graft dysfunction. There is no established paradigm for treating antibody-mediated posttransplant BSEP disease. It appears to be refractory to changes in immunosuppressant medications that would typically be effective in treating allograft rejection. Taking what is known about its pathophysiology, we designed a treatment consisting of rituximab, a chimeric monoclonal anti-CD20 antibody, in combination with intravenous immunoglobulin and plasmapheresis. Using this approach, we report the successful management of 2 patients with antibody-mediated recurrence of PFIC2 after LT.

Bile salt export pump‐reactive antibodies form a polyclonal, multi‐inhibitory response in antibody‐induced bile salt export pump deficiency

“…Absence of BSEP expression in the native liver has been postulated to be a prerequisite for the development of anti‐BSEP antibodies . In line with this, BSEP was not detectable by immunohistochemistry in native livers of patients 3‐7 (Table ).…”

“…We and others proposed that BSEP‐reactive antibodies cause cholestasis by inhibiting BSEP transport activity . Since then, only a few further cases of antibody‐induced BSEP deficiency (AIBD) have been reported . We here present a detailed analysis of the BSEP‐reactive antibody repertoire causing AIBD, and of these antibodies' functional effects, in sera from 7 more AIBD patients.…”

Familial Intrahepatic Cholestasis

“…Following the identification of BSEP antibodies in post-LT BSEP deficiency patients with cholestasis in the absence of rejection, an antibody-based treatment was suggested as potentially beneficial. Two cases of patients with BSEP deficiency following LT, had demonstrated evidence of functional BSEP deficiency treated successfully with two repeated 4-week courses of anti-cluster of differentiation CD20 monoclonal antibodies were subsequently reported [39,40].…”

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

“…In the same year, Keitel et al and Jara et al described the first four PFIC‐2 patients who developed antibodies against BSEP after OLT together with the phenotypic recurrence of BSEP deficiency, which we recently termed AIBD . Since the recognition of these antibodies in 2009, four further reports with 15 patients suffering from phenotypic recurrence of PFIC‐2 after transplantation have been published . Siebold et al calculated a prevalence of about 8% .…”

“…Retransplantation and modulation of immunosuppression did not induce sustained remission in some of these patients. In a recent report by Lin et al , a possible treatment based on rituximab and plasma exchange was described for the first time.…”