Hepatobiliary adverse events may occur with similar frequency in patients treated with biosimilar etanercept (SB4) vs originator etanercept (ETN) in inflammatory joint disease, according to study results published in Annals of Rheumatic Disease. No negative hepatobiliary safety signals of biosimilar vs originator were identified, which, the researchers noted, was “reassuring for the use of SB4 in routine care.”1

In April 2016, Denmark mandated a switch from ETN to SB4 in the treatment of inflammatory arthritis. The switch was intended as a cost-saving mechanism, and the 1-year clinical outcomes corroborated the efficacy of SB4.2 Concerns about the comparative safety of biosimilars remained as a result of a prior study suggesting that hepatobiliary adverse events occurred at a higher rate among patients receiving SB4 vs ETN.3

To explore the incidence rates (IRs) of hospital contacts as a result of hepatobiliary events during the first 6 months of treatment with ETN or SB4, and to further investigate the safety profile of SB4, researchers conducted an observational cohort study.

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Demographic and clinical characteristics were extracted from the Danish nationwide clinical register (DANBIO), data from which were linked with nationwide patient and prescription drug registries. The primary outcome was a hepatobiliary event within the first 6 months of treatment. Outcomes were reported as IRs per 100 person-years, and standardized by age and sex. Analyses were adjusted for relevant covariates, including prior comorbidities and medications. Patients were categorized into 5 treatment groups based on current regimen (ETN vs SB4) and prior exposure to biologic disease-modifying antirheumatic drugs (bDMARDs).

A total of 5708 treatment courses (ETN, 2724; SB4, 2984) were identified from 4719 unique patients. Demographic characteristics were generally comparable between ETN and SB4 groups. Among patients who received SB4, 52% had switched from prior ETN, 29% had switched from a non-ETN bDMARD, and 19% were bionaive. Among patients who received ETN, 41% were bionaive and 59% were bDMARD experienced at the time of initiation. A total of 47 hepatobiliary events were identified during follow-up, among which 21 (45%) required hospitalization. The primary hepatobiliary diagnoses were bladder stone-related diseases (n=13), elevated transaminases (n=7), liver cirrhosis (n=5), and pancreatitis (n=5). A significant percentage of patients with hepatobiliary events (n=13; 28%) received concomitant methotrexate. The IRs for hepatobiliary events were comparable across the 5 treatment courses, with no significant differences observed between patients receiving SB4 vs ETN. The adjusted IRs for patients in the bionaive ETN and bDMARD-experienced ETN groups were 1.90 (95% CI, 0.66-3.13) and 2.61 (95% CI, 1.37-3.84) per 100 person-years, respectively. In the SB4 treatment groups, adjusted IRs were 2.42 (95% CI, 0.48-4.36), 0.56 (95% CI, 0.01-1.11), and 3.01 (1.23-4.79) per 100 person-years among patients who were bionaive, switching from ETN, or switching from another bDMARD, respectively.

These results suggest a negative safety signal for hepatobiliary events in patients receiving biosimilar vs originator drugs for inflammatory joint disease. While risk was lowest among patients switching from ETN to SB4, investigators postulated that this was as a result of prior long-term exposure to ETN, rather than any protective effect of SB4. Further studies are necessary to explore the differential effects of SB4 vs ETN in the treatment of inflammatory disease.

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Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


1. Glintborg B, Georgiadis S, Loft AG, et al. Hospital contacts due to hepatobiliary adverse events in >5000 patients with inflammatory joint disease treated with originator or biosimilar etanercept (SB4): an observational nationwide study applying linkage between DANBIO and national registries [published online February 17, 2020]. Ann Rheum Dis. doi:10.1136/annrheumdis-2019-216702

2. Glintborg B, Loft AG, Omerovic E, et al. To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept one-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry. Ann Rheum Dis. 2019;78:192-200.

3. Emery P, Vencovský J, Ghil J, et al. Difference between SB4 and reference etanercept in the hepatobiliary disorders not considered to be caused by SB4: response to letter by Scheinberg and Azevedo. Ann Rheum Dis. 2016;75:e65.