LAUSR

We read with much interest the article published by Kashima and colleagues on “Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small cell lung cancer: a case report” [1]. Immune-related AEs (irAEs) affecting the biliary system on treatment with immune-oncology (I-O) agents, such PD-1/PD-L1 mAbs, are considered rare and their management remains unclear. Recently, four cases of nivolumab-related cholangitis have been reported in the literature, including three cases of “large-duct cholangitis” [2] and one case of “small-duct cholangitis” [3]. None of the patients had a history of autoimmune disorders or IgG4-related disease and all showed a predominant elevation of alkaline phosphatase and gammaglutamyltranspeptidase enzymes. The three Japanese patients with “large-duct cholangitis” developed an extensive extrahepatic biliary tract dilation without obstruction that progressed during drug administration. However, a diagnosis of primitive sclerosing cholangitis could not be definitively ruled out due to lack of data on perinuclear antineutrophil cytoplasmic antibodies (pANCA). Our case referred to as “small-duct cholangitis” did not show either intrahepatic or extrahepatic bile duct dilation and a complete serological autoimmune panel excluded any other diagnosis. However, histological findings on liver biopsies were similar in all four cases reporting a significant T cell infiltrate with a predominant CD8-positive cluster. We first speculated on the presence of different patterns of nivolumab-related cholangitis. In our opinion, the case described by Kashima and colleagues presents several aspects that differ from those previously reported (Table 1) and make a diagnosis of nivolumab-related cholangitis unlikely. Radiological imaging from a 64-year-old Japanese patient who received nivolumab for the treatment of advanced NSCLC was suggestive of cholecystitis without gallstones associated with an obstruction at the lower tract of the common bile duct. A significant rise in cholestatic enzymes and clinical symptoms also supported this diagnosis. Initially, the patient underwent several endoscopic procedures and was given empirical antibiotic therapy. Later, he presented with fever and bacteria were isolated from bile cultures. After antibiotic therapy, liver function tests initially improved, but later a new deterioration in biliary enzyme levels occurred. The authors then assumed that this event was to be considered as an immune-related toxicity and the patient was treated with high doses of corticosteroid. There was a rapid improvement in biliary enzyme levels and subsequent normalization of radiological imaging over the following months. The patient provided several bile duct biopsies/cytological smears at three different time points. The histological findings were always consistent with the presence of interstitial fibrosis and neutrophil infiltration into the bile duct. These findings were different from those reported in the other cases of immunotherapy-related cholangitis in which a CD8-positive T cell infiltrate into the liver was predominant. Furthermore, histological evidence of fibrosis would suggest a chronic disease, while the presence of a neutrophil infiltrate, associated with the detection of positive bile cultures, could be more consistent with a diagnosis of infectious disease. Finally, the presence of fibrosis and the lack of any information on serum IgG4 and pANCA levels do not rule out other forms of classic autoimmune cholangitis, such as IgG4-related disease and primitive sclerosing cholangitis. Several reports of IgG4-related disease have been described in the Japanese population, all with an excellent response to corticosteroids, as for the reported case with regression of bile strictures. This comment refers to the article available at https ://doi. org/10.1007/s0026 2-017-2062-3