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Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden
  1. Tine Iskov Kopp1,2,
  2. Bénédicte Delcoigne3,
  3. Elizabeth V Arkema3,
  4. Rikke Kart Jacobsen2,
  5. Melinda Magyari1,4,
  6. Else Helene Ibfelt2,5,
  7. Henning Locht6,
  8. Finn Sellebjerg4,
  9. Rene Lindholm Cordtz7,
  10. Dorte V Jensen7,
  11. Johan Askling3,8,
  12. Lene Dreyer9,10
  1. 1 The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark
  2. 2 Center for Clinical Research and Prevention, Frederiksberg Hospital, Frederiksberg, Denmark
  3. 3 Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  4. 4 Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, Kobenhavn, Denmark
  5. 5 Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark
  6. 6 Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark
  7. 7 Center for Rheumatology and Spine Diseases - Gentofte, Rigshospitalet, Hellerup, Denmark
  8. 8 Rheumatology, Karolinska University Hospital, Stockholm, Sweden
  9. 9 Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
  10. 10 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
  1. Correspondence to Dr Tine Iskov Kopp, The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet Glostrup, 2600 Glostrup, Denmark; tine.iskov.kopp{at}


Objectives To investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases.

Methods Cohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000–2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country.

Results Among 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar.

Conclusions Use of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year.

  • anti-TNF
  • rheumatoid arthritis
  • psoriatic arthritis
  • ankylosing spondylitis
  • outcomes research

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  • Handling editor Josef S Smolen

  • TIK and BD contributed equally.

  • Contributors LD and JA conceived the idea for the study and all authors planned the study collaboratively. TIK, BD, EVA, RKJ, JA and LD developed the analysis plan. TIK, BD, EVA and RKJ performed management of data and statistical analyses. MM and FS provided specific input on neuroinflammatory diseases. HL, JA and LD provided specific input on rheumatic diseases. RLC and DVJ provided input on DANBIO data. JA and LD provided funding. TIK and BD wrote the first draft of the manuscript. All authors reviewed the results and critically reviewed the manuscript for intellectual content. All authors approved the final version of the manuscript.

  • Funding This study was funded by Program for Clinical Research Infrastructure (PROCRIN) established by the Novo Nordisk and Lundbeck Foundations, and received funding from the Swedish Research Council, The independent Research Fund Denmark, and from the Karolinska Institutet Region Stockholm funds (ALF).

  • Competing interests MM has received grants from Novartis and Biogen, and has received personal fees from Novartis, Biogen, Merck, Sanofi Genzyme and Teva. FS has received grants and personal fees from Biogen, Merck, Novartis, Sanofi Genzyme and Roche. JA has received grants from Abbvie, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB. LD has received grants from BMS and has received personal fees from Eli Lilly and Galderma. TIK, BD, EVA, RKJ, EHI, RLC, HL and DVJ have nothing to disclose.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval According to Danish and Swedish legislation, the registration and publication of data from national registers do not require patient consent or approval by Ethics Committees. Approval was given by the Danish Data Protection Agency ( 04422, with I-Suite no: CSU-FCFS-2016-001).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available.