The use of tumor necrosis factor inhibitors (TNFis) is associated with an increased risk for incident neuroinflammatory disease in patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS) but not in patients with rheumatoid arthritis (RA), according to findings published in the Annals of the Rheumatic Diseases.

This dual-nation prospective cohort study was designed to assess whether the incident neuroinflammatory disease risk observed in patients with rheumatic diseases is coincidentally or causally linked to TNFi use. The researchers evaluated the risk by specific TNFi treatments and individual rheumatologic conditions. Data from patients with inflammatory arthritis were collected from national health and clinical registers in Sweden and Denmark. Two cohort studies were performed in parallel, with analyses performed for each country.

Out of a total 175,520 combined patients with AS, PsA, or RA, 25% (n=43,909) were exposed to TNFi treatment at some time during follow-up. The crude incidence rate for all types of neuroinflammatory events combined across all patients with RA in Sweden who were exposed to TNFis was 0.37 per 1000 person-years compared with 0.39 per 1000 person-years among patients who were not exposed. In Denmark, the crude incidence rate was 0.39 per 1000 person-years for patients with RA who were exposed to TNFis compared with 0.28 per 1000 person-years among those who were not exposed. In the Swedish cohort, no association was found between TNFi treatment and neuroinflammatory event risk (hazard ratio [HR], 0.97; 95% CI, 0.72-1.33), and a higher but not significantly increased risk was seen in the Danish cohort (HR, 1.45; 95% CI, 0.74-2.81).

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Compared with patients with AS and PsA who were not exposed to TNFi treatment, a significantly increased risk for all types of neuroinflammatory events was seen in the cohorts of individuals with AS and PsA who were exposed to TNFi treatment, with a 50% increase in risk in the Swedish cohort (HR, 1.50; 95% CI, 1.07-2.11) and a 3.4-fold increase in the Danish cohort (HR, 3.41; 95% CI, 1.30-8.96). Among TNFi-exposed patients who experienced a neuroinflammatory event, the mean time to event was 3.8 years (interquartile range, 1.7-5.9) in the Swedish cohort and 3.1 years (interquartile range, 1.4-8.6) in the Danish cohort.

Men showed a 2-fold higher risk for neuroinflammatory events compared with women (5.81 vs 2.50) in the Danish cohort (the HRs were similar between Swedish men and women: 1.37 vs 1.67), but sex did not appreciably change the HRs for associations between TNFi treatment and outcomes.

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The study investigators concluded that “[t]his information will be important for risk communication and evaluation in clinical practice, even though the absolute risk is low. The underlying biological mechanism needs to be further explored to [characterize] the mechanism of action and to enable identification of susceptible patients.”

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


Kopp TI, Delcoigne B, Arkema EV, et al. Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden. Ann Rheum Dis. 2020;79:566-572.