Exposure to specific tumour necrosis factor inhibitors and risk of demyelinating and inflammatory neuropathy in cohorts of patients with inflammatory arthritis: a collaborative observational study across five Nordic rheumatology registers

Abstract

Objective: To compare incidences of neuroinflammatory events, including demyelinating disease (DML), inflammatory polyneuropathies (IPN) and multiple sclerosis (MS), in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA; including psoriatic arthritis) starting a tumour necrosis factor inhibitor (TNFi), investigating whether monoclonal TNFi antibodies (other TNFis (oTNFis)) confer higher risk than etanercept.

Methods: This is an observational cohort study including patients from the five Nordic countries starting a TNFi in 2001-2020. Time to first neuroinflammatory event was identified through register linkages. We calculated crude incidence rates (cIR) per 1000 person-years and used multivariable-adjusted Cox regression to compare incidences of neuroinflammatory events overall and for DML, IPN and MS with oTNFi versus etanercept. We further examined individual TNFis and indications.

Results: 33 883 patients with RA and 28 772 patients with SpA were included, initiating 52 704 and 46 572 treatment courses, respectively. In RA, we observed 135 neuroinflammatory events (65% DML) with cIR of 0.38 with oTNFi and 0.34 with etanercept. The HR of oTNFi versus etanercept was 1.07 (95% CI 0.74 to 1.54) for any neuroinflammatory event, 0.79 (95% CI 0.51 to 1.22) for DML, 2.20 (95% CI 1.05 to 4.63) for IPN and 0.73 (95% CI 0.34 to 1.56) for MS. In SpA, we observed 179 events (78% DML) with cIR of 0.68 with oTNFi and 0.65 with etanercept. The HR for any neuroinflammatory event, DML, IPN and MS was 1.06 (95% CI 0.75 to 1.50), 1.01 (95% CI 0.68 to 1.50), 1.28 (95% CI 0.61 to 2.69) and 0.94 (95% CI0.53 to 1.69), respectively.

Conclusion: The cIRs of neuroinflammatory events are higher in SpA than in RA, but the choice of specific TNFi does not seem to play an important role in the risk of neuroinflammatory events.

Keywords: Arthritis, Psoriatic; Arthritis, Rheumatoid; Spondylitis, Ankylosing; Tumor Necrosis Factor Inhibitors.

Figure 1

Number of events, person-years and crude incidence rates of neuroinflammatory events in patients with RA. The values of HR (95% CI) from the comparison of oTNFi with etanercept with Cox regression analyses are displayed. The analyses were adjusted for age, sex, calendar period of TNFi start, disease duration, CRP and concomitant use of methotrexate, and stratified by the number of b/tsDMARDs the patients had been exposed to prior to the TNFi start. Displayed HRs resulted from a random-effects meta-analysis of the analyses performed in Denmark (Danish data) and in Sweden (pooled data from Finland, Iceland, Norway and Sweden, with Cox regressions also stratified by country). ‘Any’ refers to any neuroinflammatory event (DML, IPN or MS). b/tsDMARD, biologic or targeted synthetic disease-modifying antirheumatic drug; CRP, C reactive protein; DML, demyelinating disease; ETN, etanercept; IPN, inflammatory polyneuropathy; MS, multiple sclerosis; oTNFi: other tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, infliximab, golimumab); pyrs, person-years; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor.

Figure 2

Number of events, person-years and crude incidence rates of neuroinflammatory events in patients with SpA. The values of the HR (95% CI) from the comparison of oTNFi with etanercept with Cox regression analyses are displayed. The analyses were adjusted for age, sex, calendar period of TNFi start, disease duration, CRP and concomitant use of methotrexate, and stratified by the number of b/tsDMARDs the patients had been exposed to prior to the TNFi start. Displayed HRs resulted from a random-effects meta-analysis of the analyses performed in Denmark (Danish data) and in Sweden (pooled data from Finland, Iceland, Norway and Sweden, with Cox regressions also stratified by country). ‘Any’ refers to any neuroinflammatory event (DML, IPN or MS). b/tsDMARD, biologic or targeted synthetic disease-modifying antirheumatic drug; CRP, C reactive protein; DML, demyelinating event; ETN, etanercept; IPN, inflammatory polyneuropathy; MS, multiple sclerosis; oTNFi, other tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, infliximab, golimumab); pyrs, person-years; SpA, spondyloarthritis (including psoriatic arthritis and ankylosing spondylitis); TNFi, tumour necrosis factor inhibitor.