Hepatitis E during Tocilizumab Therapy in a Patient with Rheumatoid Arthritis: Case Report and Literature Review

Hepatitis E is an acute self-limiting disease caused by hepatitis E virus (HEV). Recent reports show that HEV can induce chronic hepatitis or be reactivated in immunocompromised hosts. We report a 63-year-old woman with rheumatoid arthritis (RA) who developed hepatitis E during treatment with tocilizumab. Analysis of serially stocked serum samples confirmed that hepatitis was caused by primary infection with HEV and not by viral reactivation. Her liver function improved after discontinuing tocilizumab and remained within the normal range without reactivation of HEV for >5 years after restarting tocilizumab. We also reviewed the published cases of hepatitis E that developed during RA treatment.


Introduction
Hepatic disorders are some of the most common complications that arise during rheumatoid arthritis (RA) treatment. Routine liver enzyme testing is recommended to detect the side effects of disease-modifying antirheumatic drugs (DMARDs) as well as the reactivation of viruses such as hepatitis type B (HBV), hepatitis type C (HCV), and cytomegalovirus [1,2].
Hepatitis E is a disease of the liver that is caused by hepatitis type E virus (HEV) infection. HEV usually induces acute self-limiting hepatitis in healthy individuals. However, HEV is known to induce chronic hepatitis in immunocompromised hosts, including patients with HIV infection, chemotherapy recipients, and organ transplant recipients [3,4]. In addition, HEV deterioration has been reported in patients after allogenic stem cell transplantation [5,6], despite low risk of deterioration [7].
Here, we report a case of hepatitis E that developed during tocilizumab therapy for RA. In this case, we sequentially determined the serum titers of HEV antibodies and RNA before and after the onset of hepatitis using stocked serum samples. In addition, we reviewed the published cases of hepatitis E that occurred during RA treatment with DMARDs.

Case Presentation
A 63-year-old woman visited our outpatient clinic because of general malaise that lasted 6 days. She developed RA at the age of 60 years and had been treated with 400 mg monthly intravenous tocilizumab for the past 10 months and 3 mg/day prednisolone. She had no history of blood transfusion, alcohol use, travel abroad, or raw meat intake, and her joints were not tender or swollen. Disease Activity Score 28-joint count C reactive protein was 1.13. Laboratory data revealed elevated liver enzyme levels: AST, 338 IU/L; ALT, 523 IU/L; ALP, 377 IU/L; and c-GTP, 68 IU/L. Blood counts, total protein, albumin, total bilirubin, electrolytes, renal tests, C reactive protein, and coagulation test results were almost within normal ranges. Her serum HBV nucleic acid levels were monitored regularly to detect HBV reactivation because she tested positive for antibodies to HBV surface and core antigens without HBs antigen before the initiation of tocilizumab. At admission, HBV DNA levels were within normal range. Tests to detect antibodies to hepatitis A and C were negative. Tests to detect antibodies to Epstein-Barr virus and cytomegalovirus were both negative for immunoglobulin M (IgM) but positive for immunoglobulin G (IgG). Abdominal ultrasound revealed normal liver morphology. e patient was diagnosed with HEV infection (genotype 3) because tests to detect anti-HEV immunoglobulin A (IgA) antibody and HEV RNA in her sera were both positive. Tocilizumab, pregabalin, eldecalcitol, and teriparatide were discontinued, and stronger neo-minophagen C and ursodeoxycholic acid were administered. Liver enzyme levels decreased and returned to normal 3 weeks after admission, and she was discharged from our hospital. Results of HEV RNA tests were negative 6 weeks after admission. Tocilizumab and eldecalcitol were reinitiated 4 weeks after liver enzyme normalization. RA remained in remission, and liver enzymes remained stable for the subsequent 5 years under tocilizumab therapy.
Because she had been a participant in a prospective clinical study to investigate the incidence of HBV reactivation in patients receiving immunosuppressive and/or anticancer therapies [8], her sera that was collected prior to hepatitis E onset had been stored. e use of serially stocked sera for HEV detection was approved by the Ethics Committee of Gunma University Hospital (#15-61). We examined her serum for anti-HEV antibodies and HEV RNA before and after admission (Table 1). Neither anti-HEV antibodies nor HEV RNA was detected in the preadmission samples. In contrast, all of them were positive at admission. Anti-HEV IgM and IgA antibody levels peaked 1 week after admission and declined thereafter. Anti-HEV IgG antibody levels remained elevated until the final observation at 57 months. HEV RNA was detected at 0, 2, and 3 weeks after admission and was undetectable thereafter.

Discussion
HEV was previously believed to cause acute hepatitis but not chronic hepatitis. However, Kamar et al. first reported that chronic HEV infection was observed in patients after organ transplantation [3]. ey further reported that HEV infection caused chronic hepatitis in >60% of solid-organ transplant recipients [9]. Chronic HEV infection was also reported in patients with HIV infection and in a patient with malignant lymphoma treated with rituximab [4,10]. In addition, HEV persistent infection has been reported in recipients of bone marrow transplant under severe immunosuppression [5][6][7]. Recently, biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) are frequently used in RA treatment. Treatment with bDMARDs is reported to increase the risk of hepatitis B virus reactivation in patients with RA [11]. erefore, chronic transformation of hepatitis E may occur in patients with RA who are treated with bDMARDs or tsDMARDs. In our case, sequential analysis of anti-HEV antibodies and HEV RNA using stocked serum samples clearly confirmed that our patient developed hepatitis as a result of primary acute HEV infection, but not recurrence or chronic infection of HEV. e clinical course of our patient was self-limiting, and the virus was eradicated from the serum without chronic transformation. In addition, there was neither recurrence of hepatitis nor persistent infection of HEV infection during the following 5 years, even after the reintroduction of tocilizumab.
e case reports of hepatitis E infection in patients with RA are accumulating [12][13][14][15][16][17][18][19][20][21]. Table 2 summarizes published cases of hepatitis E developed during the treatment of RA with DMARDs. Of 26 cases including ours, 20 were treated with bDMARDs or tsDMARDs with or without conventional synthetic DMARDs (csDMARDs) and 6 cases were treated with csDMARDs alone. Low-dose steroids were used in 16 cases. In most cases, DMARDs were discontinued for   Case Reports in Rheumatology 3 a certain period after the diagnosis of hepatitis. Temporal withdrawal of DMARDs may help the immune system to recover and eliminate HEV. In most patients, liver function was normalized without antiviral therapy. However, 1 patient (case 1) died of fulminant hepatitis, despite treatment with plasma exchange and continuous hemofiltration [12]. e HEV genotype detected in this patient was genotype 4, which is known to be more virulent than genotype 3. In addition, a male patient (case 25) who was administered adalimumab and methotrexate developed chronic hepatitis E [21]. e routine testing revealed elevated liver enzyme levels, and methotrexate, but not adalimumab, was discontinued. Eight months later, he was diagnosed with HEV infection, and adalimumab was discontinued. However, serum HEV RNA remained positive for more than 5 months; therefore, he was treated with ribavirin for 42 days until the test results for serum HEV RNA were negative [21].
In transplant recipients with chronic HEV infection, antiviral therapy with interferon-α and ribavirin as monotherapy or in combination is recommended if immunosuppressive therapy has to be continued or viral clearance is difficult to achieve even after weakening immunosuppression [22,23]. In patients with RA who are treated with DMARDs as listed above, only 4 cases were treated with ribavirin and 3 of them had been treated with rituximab. Another patient had been treated with adalimumab before and after notification of elevated liver enzymes for several months and ultimately developed chronic hepatitis E, as described above [14,15,19,21]. Based on these results, antiviral therapy may be considered only in high-risk patients: patients with HEV (genotype 4), those who had been treated with long-lasting and immunosuppressive DMARDs such as rituximab, and those with severe or chronic hepatitis. Further investigation is to clarify the adequate use of ribavirin in acute hepatitis E patients taking DMARDs.
In summary, we presented a case of RA with hepatitis E that developed during tocilizumab therapy, and we reviewed published cases of hepatitis E among patients with RA on DMARDs treatment. In RA patients whose liver dysfunction was detected at routine examination, the possibility of HEV infection should be considered. In a case of hepatitis E, discontinuation of bDMARDs or tsDMARDs is recommended, and administration of ribavirin may be necessary in high-risk patients. In addition, in our case, tocilizumab was safely used after normalization of liver function for a long term without persistent infection of HEV. Consent e patient's written informed consent for publication of information about her was obtained.

Disclosure
Parts of this manuscript were reported in Kanto Riumachi (2016; 1: 96-102) in Japanese, from the proceedings of the 47th Kanto Riumachi Conference (Tokyo, Japan).

Conflicts of Interest
Keiju Hiromura has received an honoraria for lectures from Chugai Pharmaceutical, Co., Ltd. Satoshi Mochida has received an honoraria for lectures from Bristol-Myers Squibb, consigned/joint research expenses from Bristol-Myers Squibb and Tanabe Mitsubishi Pharma Co., and scholarship donations from Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., and Takeda Pharmaceutical Co. Ltd. e authors declare that they have no conflicts of interest.