• DMARDs (biologic)
• epidemiology
• Anti-TNF
• rheumatoid arthritis

Recent international guidelines recommend the use of biosimilar biological drugs on similar terms as their corresponding originators, including switching from a bio-originator to the biosimilar.1 However, the comparative safety of biosimilars in patients with inflammatory joint diseases (IJD) in routine care is still debated.2 In a phase 3 randomised trial among patients with rheumatoid arthritis, biosimilar etanercept (SB4) had slightly more hepatobiliary adverse events compared with the originator (ETN), possibly explained by differences in patients’ comorbid diseases and comedication use.3 The occurrence of, for example, hepatobiliary safety events is likely to differ across indications (due to differences in age, body weight, use of methotrexate, comedication, etc) and has not been explored in etanercept-treated patients with psoriatic arthritis or axial spondyloarthritis.4

In April 2016, a mandatory switch from ETN to SB4 was performed in Denmark to save costs and the 1-year clinical outcomes were reassuring.5 The high penetration of biosimilars in Denmark, longitudinal follow-up of adult patients with IJD in the nationwide DANBIO registry and the possibility of linkage to national registries give optimal conditions for exploring safety across treatments.5

In this observational cohort study, we aimed to explore incidence rates (IRs) of hospital contacts (hospitalisations or outpatient care) due to hepatobiliary events during the first 6 months of routine treatment with ETN or SB4 in IJD. It was beyond the aim to explore milder/transient hepatobiliary events not causing hospital contact. Planned calculations of relative risks and exploration of characteristics associated with the outcome were omitted due to few events. Patients were divided into five groups according to current use of either ETN or SB4 and biological treatment history (footnote table 1) including the subgroup of SB4 treated patients that switched from prior ETN (=non-medical switchers). Ethics approval was not required (epidemiological research).

Patient characteristics and disease activity at treatment start (=baseline) were retrieved from DANBIO. Prior comorbidities and use of prescription medication that might affect hepatobiliary events and the main outcomes (hospital contacts due to hepatobiliary events (ICD-10 codes: online supplementary table S1) from baseline until 6 months after treatment start) were identified through linkage to the Danish National Patient Registry and National Prescription Drug Registry.6 Exposure time was defined as: from baseline until first hepatobiliary event, 6 months after treatment start, treatment withdrawal, death or emigration, whichever came first. Outcomes are presented as IRs per 100 person-years (crude and gender and age standardised).

A total of 5708 treatment courses (2724 ETN/2984 SB4) in 4719 unique patients were identified (table 1). Among SB4-treated patients, 52% were non-medical switchers (table 1). At baseline, use of concomitant medication and comorbidities were similar in the five groups.

We identified 47 hepatobiliary events during the follow-up whereof 21 were hospitalised (table 1). Main events were gall-bladder stone-related diseases (13 patients), elevated transaminases (n=7), liver cirrhosis (n=5), pancreatitis (n=5) (online supplementary table S2). The IRs were low and lowest in non-medical switchers. Among the 47 patients with hepatobiliary events, 13 (28%) received concomitant methotrexate.

In registries with high completeness, real-world incidence of hepatobiliary events was investigated in >5000 patients with IJD receiving originator or SB4. The results are expected to be representative of other real-life cohorts treated with etanercept. Follow-up was restricted to the first 6 months of treatment since a time-varying risk was expected. Risk was lowest in the non-medical switch group probably due to prior long-term treatment with ETN (‘healthy survivor effect’).5

Overall, we identified no negative hepatobiliary safety signal of biosimilar versus originator drug. This is reassuring for the use of SB4 in routine care.