Risk of neurological adverse events during tumour necrosis factor inhibitor treatment for arthritis: a population-based cohort study from danbio and artis

Background Tumor necrosis factor alpha inhibitors (TNFi) have successfully been used for the treatment of immune-mediated inflammatory disorders including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) since 1998. However, several case reports and series have indicated that different neurological disorders including multiple sclerosis (MS), inflammatory neuropathies, demyelinating diseases and optic neuritis may be a serious, although rare, adverse event following TNFi treatment. The relationship is complex, as some studies show that RA is protective of MS and vice versa.Objectives To investigate the association between new-onset neurological events following TNFi treatment in arthritis patients compared to non-TNFi-treated arthritis patients from Denmark and Sweden.Methods 40,927/62,702 patients registered with a diagnosis of either RA, AS or PsA in DANBIO/ARTIS between January 1, 2000 and January 20, 2017 were included. Complete follow-up on mortality, emigration and incident neurological diseases suspected to be associated with use of TNFi until May 10, 2017 were obtained by linkage to the Danish and Swedish National Patient Registry and the Civil Registration Systems. Cox proportional hazard models were used to examine the association between use of TNFi and risk of a neurological event.Results The DANBIO/ARTIS arthritis cohorts contributed 612,347 person-years of observation and 221 patients were diagnosed with demyelinating disease or inflammatory neuropathy during follow-up with 117 cases among TNFi-treated patients and 104 cases among non-TNFi-treated patients. TNFi treatment among RA patients was not associated with an increased risk of a neurological event (DANBIO: HR=1.09, 95% Confidence Interval (CI) 0.60-1.99)/(ARTIS:HR=0.83, 95%CI 0.52-1.35) adjusted for age, gender and year of inclusion. However, TNFi-treated PsA and AS patients had an increased risk of neurological events (DANBIO:HR=2.57, 95%CI 1.17-5.65)/(ARTIS:HR=2.17, 95%CI 0.88-5.35). In TNFi-treated PsA/AS patients, 7 cases of inflammatory polyneuropathies were observed in DANBIO/ARTIS respectively versus 1 and 0 cases among non-TNFi treated. In on-drug models, the HR for neurologic events was 1.17 (ARTIS 95% CI: 0.41-3.35) and 1.66 (DANBIO 95% CI: 0.70-3.92) in PsA/AS.Conclusion The use of TNFi for the treatment of arthritis may be associated with increased risk of demyelinating disease or inflammatory neuropathies among patients with PsA and AS. Since these events are rare, larger multicentre studies are warranted to further characterize the risk.Acknowledgement The study is funded by FOREUM, NordForsk and Independent Research Fund DenmarkDisclosure of Interests Tine Iskov Kopp : None declared, Elizabeth Arkema: None declared, René Cordtz: None declared, Bénédicte Delcoigne: None declared, Johan Askling Grant/research support from: Karolinska Institutet (JA) has or has had research agreements with the following pharmaceutical companies, mainly in the context of the ATRIS national safety monitoring programme for rheumatology biologicals: Abbvie, BMS, MSD, Eli Lilly, Pfizer, Roche, Samsung Bioepis, and UCB., Consultant for: Karolinska Institutet has received remuneration for JA participating in ad boards arranged by Lilly, Novartis, and Pfizer., Lene Dreyer Consultant for: MSD, UCB and Janssen Pharmaceuticals, Speakers bureau: MSD, UCB and Janssen Pharmaceuticals, Speakers bureau: UCB, MSD, Eli Lilly and Janssen Pharmaceuticals.