Abstract
This case study describes a patient in whom administration of an anti-CD20 antibody to treat multiple sclerosis appears to have precipitated liver failure.
Ocrelizumab (Ocrevus [Roche-Genentech]), a second-generation humanized anti-CD20 antibody, has been recently approved for multiple sclerosis (MS). Echoviruses and other enteroviruses have been associated with life-threatening infections in patients receiving anti-CD20 antibodies other than ocrelizumab.1,2,3,4 In this case study, we report a case of fulminant echovirus 25–associated hepatitis in a patient with relapsing-remitting MS who received ocrelizumab monotherapy.
Results
A 44-year-old white woman with relapsing-remitting MS received 600 mg of ocrelizumab intravenously every 24 weeks for 4.5 years as part of the OPERA II trial.5 At screening, the patient tested positive for anti–hepatitis B virus (HBV) core and surface antibodies, while serum HBV surface antigen and HBV DNA test results were negative. Serum immunoglobulin levels were repeatedly found to be normal.
In July 2017, the patient and a person in close contact with her developed watery diarrhea. While the other person recovered quickly, the patient reported persistent febrile diarrhea (2 to 4 episodes/day) associated with a self-limiting maculopapular rash. For fever control, patient took 1000 mg of acetaminophen per day for 10 days. Two weeks thereafter, she was hospitalized. Blood tests showed increased alanine aminotransferase and aspartate aminotransferase levels (1847 and 2484 U/L, respectively; to convert either value to microkatals per liter, multiply by 0.0167), without cholestasis. An abdomen ultrasonographic examination and computed tomographic scan were normal. Three days later, her liver enzyme levels markedly improved (alanine aminotransferase, 954 U/L; aspartate aminotransferase, 281 U/L), despite remitting fever and persistent diarrhea. On day 7 after admission, alanine and aspartate aminotransferase levels peaked to 6241 U/L and 9799 U/L, respectively, with increased bilirubin (total, 4 mg/dL; direct, 2.9 mg/dL; to convert either value to micromoles per liter, multiply by 17.104) and signs of coagulopathy (prothrombin time, 24%; international normalized ratio, 2.95). Owing to progression to liver failure, she received a liver transplant 11 days after admission.
The main infectious causes of acute liver failure were excluded. Reactivation of resolved HBV infection was ruled out by the negative serum HBV surface antigen and HBV DNA test results. Serological and serum molecular tests excluded hepatitis A, C, and E; herpesviruses 6, 7, and 8; and HIV, cytomegalovirus, Epstein-Barr virus, parvovirus B19, and adenovirus. Stool samples tested negative for hepatitis A, adenovirus, rotavirus, and norovirus. Autoimmune hepatitis, suspected because of positive test results for antinuclear and antismooth muscle antibodies, was unlikely owing to the absence of liver or kidney microsomal antibodies and antisoluble liver antigen and liver pancreas antibodies.
Acetaminophen-associated toxic effects were excluded because severe liver damage usually occurs with administration of more than 4000 mg per day.6 Other toxic causes were excluded based on the patient’s history. A direct liver adverse event associated with ocrelizumab was unlikely, since the patient had been treated for more than 4 years.
The possibility of an enterovirus infection was investigated. Two plasma samples collected 8 days apart (11 and 2 days before the transplant procedure) tested positive for enterovirus RNA, and this was subsequently identified as echovirus 25. Stool samples tested negative for enteroviral RNA.
In the patient’s native liver tissue, an HBV DNA test result was negative, while a test result for enterovirus RNA was positive. A phylogenetic analysis revealed that both serum and native liver samples harbored echovirus 25.
Up to 12 months after the transplant, no relapse of echovirus 25 infection was observed clinically or in molecular test results. Although ocrelizumab was permanently withdrawn, the patient did not show signs of MS activity or disability progression, possibly owing to the immunosuppressive effects of basiliximab and tacrolimus, which were given to prevent liver rejection.
Discussion
We report what is, to our knowledge, the first case of fulminant hepatitis owing to echovirus 25 in a patient with MS who was treated with ocrelizumab. A few severe enteroviral infections were previously reported after B-cell depletion, mainly in patients with hematological conditions.1,2,3,4 Whereas meningoencephalitis was the most common manifestation, 3 cases of fulminant hepatitis were reported, of which 2 involved bimodal liver enzyme elevation, as this case did (Table).1,2,3
Table. Confirmed Cases of Enterovirus-Associated Fulminant Hepatitis in Association With Anti-CD20 Agents.
| Source, Year | Anti-CD20 Agent | Patient, No. | Indication for Anti-CD20 Agent | Enterovirus-Associated Disease | ||||
|---|---|---|---|---|---|---|---|---|
| Clinical Presentation | Type of Enterovirus Identified | Diagnosis | Treatment for Enteroviral Infection | Outcome | ||||
| Lefterova et al,1 2013 | Rituximab | 1 | B-cell non-Hodgkin lymphoma | Meningo-encephalitis and fulminant hepatitis | Echovirus 18 | Real-time polymerase chain reaction in cerebrospinal fluid, plasma, and liver tissue | Plasmapheresis | Death |
| Morgan et al,2 2015 | Rituximab | 1 | Follicular lymphoma | Fulminant hepatitis | Echovirus 9 | Real-time polymerase chain reaction in plasma and liver tissue | Intravenous IgG | Recovery with sequelae (memory loss and fatigue) |
| Bajema et al,3 2017 | Rituximab | 1 | Nephrotic syndrome with minimal change disease | Meningo-encephalitis and fulminant hepatitis | Echovirus 9 | Real-time polymerase chain reaction in plasma and liver tissue | None | Death |
Because ocrelizumab is a novel, high-efficacy disease-modifying therapy for MS, it will probably be extensively used. However, it may impair clearance of enterovirus infections via B-cell depletion. Thus, in the case of compatible symptoms, tests should be conducted for enteroviruses. Given the bimodal clinical presentation (ie, the patient had a severe rebound of liver enzyme levels after initial improvement), patients receiving ocrelizumab with enteroviral infection need close follow-up.
References
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