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Demyelinating Risks With Anti-TNF Vary in Rheumatic diseases - MedPage Today

A computer rendering of neurons

A computer rendering of neurons

Patients with certain types of arthritic conditions were at elevated risk for developing neuroinflammatory events if treated with tumor necrosis factor (TNF) inhibitors, a large prospective cohort study conducted in Denmark and Sweden found.

Among Swedish patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA) who were exposed to TNF inhibitors, there was a 50% greater risk for any neuroinflammatory event compared with unexposed patients (HR 1.50, 95% CI 1.07-2.11), according to Tine Iskov Kopp, PhD, of the department of neurology at Rigshospitalet Glostrup in Denmark, and colleagues.

And among Danish patients with AS or PsA who used TNF inhibitors, the risk increased 3.4-fold (HR 3.41, 95% CI 1.30-8.96), the researchers reported online in Annals of the Rheumatic Diseases.

However, there was no significantly increased risk for patients with rheumatoid arthritis (RA), with hazard ratios of 0.97 (95% CI 0.72-1.33) in Sweden and 1.45 (95% CI 0.74-2.81) in Denmark.

The inflammatory cytokine TNF has been implicated in the pathogenesis of Multiple Sclerosis (MS), with high levels present in the cerebral lesions and cerebrospinal fluid of patients. In addition, MS patients who were treated with TNF inhibitors in early clinical trials showed disease exacerbations.

Case reports also have suggested that patients with arthritic diseases may have an increased risk of neuroinflammatory disorders, but the risk seems to be dependent on the specific type of arthritis. For instance, regardless of treatment exposures, patients with PsA appear to have an increased risk for MS, whereas patients with RA are reported to have a lower risk.

To more fully explore the risks for these events with and without TNF inhibitor exposure in patients with RA or PsA/AS, Kopp and colleagues analyzed data from the Danish DANBIO register and the Swedish Rheumatology Quality Register for outcomes among rheumatic patients receiving biologic therapies during the years 2000 to 2017. The two countries' national patient registers provided information on the incidence of neuroinflammatory events.

The analysis included 175,520 patients with RA, PsA, or AS in the two cohorts, of whom 43,909 were treated with TNF inhibitors at any time during follow-up. Neuroinflammatory events were classified as MS, other demyelinating diseases such as optic neuritis, or polyneuropathy events.

In the AS/PsA group, the rate of demyelinating events was 141 per 447,906 person-years in Sweden and 24 per 60,835 person-years in Denmark. For MS, the rates were 48 per 448,324 person-years and 7 per 60,894 person-years, respectively, and for polyneuropathy events, the rates were 55 per 448,497 and 8 per 60,891, respectively.

For all three categories of neuroinflammatory events combined, the incidence rates were 0.59 per 1,000 person-years in Sweden and 0.87 per 1,000 person-years in Denmark for TNF inhibitor users compared with 0.40 per 1,000 and 0.19 per 1,000 among non-users.

The time to any event among exposed patients was 3.8 years in the Swedish group and 3.1 years in the Danish group, and patient ages at the time of the event were 43 and 46, respectively. In a sensitivity analysis, no association was seen between age and risk of events. Patient sex also did not appear to influence the risk, the authors observed.

Among RA patients, the incidence rates of any neuroinflammatory event were 0.37 per 1,000 person-years in Sweden and 0.39 per 1,000 in Denmark for exposed patients compared with 0.39 and 0.28 per 1,000 among unexposed patients.

"In this large population-based, prospective cohort study, we observed an increased risk of neuroinflammatory events suggestive of demyelination following treatment with TNF inhibitors among patients with PsA or AS compared with non-exposed PsA or AS patients, although the risk was very low," the researchers stated.

The results also supported the concept that the risks differ among the different types of arthritic diseases.

The potential mechanisms by which TNF inhibitor use influences the risk of demyelinating events are not fully understood, but theories that have been proposed include the inability of the drugs to penetrate the blood-brain barrier and interference with cytokines such as interleukins 10 and 12.

The underlying biology of demyelination with anti-TNF exposure warrants further study "to characterize the mechanism of action and to enable identification of susceptible patients," the authors concluded.

A limitation of the study, they said, was the possibility of confounding by indication.

Disclosures

The study was funded by the Program for Clinical Research Infrastructure established by the Novo Nordisk and Lundbeck Foundations, the Swedish Research Council, the Independent Research Fund Denmark, and the Karolinska Institute.

The authors reported financial relationships with Novartis, Biogen, Merck, Sanofi Genzyme, Teva, Biogen, Roche, AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, Samsung Bioepis, UCB, and Galderma.

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Tuesday, 02 June 2020

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