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

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.

[1]  C. Turesson,et al.  Short-term, intermediate-term and long-term risks of acute coronary syndrome in cohorts of patients with RA starting biologic DMARDs: results from four Nordic countries , 2022, Annals of the Rheumatic Diseases.

[2]  F. Piehl,et al.  Demyelinating events following anti‐tumor necrosis factor alpha therapy: Rare but challenging to treat , 2022, European journal of neurology.

[3]  M. AlKahlout,et al.  Demyelinating Neurological Adverse Events following the Use of Anti-TNF-α Agents: A Double-Edged Sword , 2022, Case reports in neurological medicine.

[4]  Magdalena Świder,et al.  Neurological Complications of Biological Treatment of Psoriasis , 2022, Life.

[5]  A. Kermode,et al.  Central Nervous System Demyelination Related to Tumour Necrosis Factor Alpha Inhibitor , 2022, Multiple sclerosis journal - experimental, translational and clinical.

[6]  M. Elleuch,et al.  Acute transverse myelitis revealing ankylosing spondylitis: A case report and literature review , 2021, Clinical case reports.

[7]  K. Lambertsen,et al.  The Role of Non-Selective TNF Inhibitors in Demyelinating Events , 2021, Brain sciences.

[8]  E. Pelechas,et al.  Neuroinflammatory events after anti-TNFα therapy , 2020, Annals of the Rheumatic Diseases.

[9]  J. Primdahl,et al.  EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update , 2020, Annals of the Rheumatic Diseases.

[10]  B. Weinshenker,et al.  Association Between Tumor Necrosis Factor Inhibitor Exposure and Inflammatory Central Nervous System Events , 2020, JAMA neurology.

[11]  R. Jacobsen,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 , 2020, Annals of the Rheumatic Diseases.

[12]  B. Gudbjornsson,et al.  Outcomes and Safety of Tumor Necrosis Factor Inhibitors in Reactive Arthritis: A Nationwide Experience from Iceland , 2020, The Journal of Rheumatology.

[13]  Tsutomu Takeuchi,et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update , 2020, Annals of the Rheumatic Diseases.

[14]  Hsuan-Chia Yang,et al.  Increase Risk of Multiple Sclerosis in Patients with Psoriasis Disease: An Evidence of Observational Studies , 2019, Neuroepidemiology.

[15]  S. Farshad,et al.  Rheumatoid Meningoencephalitis: A Feared Condition in the Era of TNF Blockers , 2018, Case reports in rheumatology.

[16]  H. Stan,et al.  Pearls & Oy-sters: Rheumatoid meningitis occurring during treatment with etanercept , 2018, Neurology.

[17]  L. Jacobsson,et al.  Opportunities and challenges for real-world studies on chronic inflammatory joint diseases through data enrichment and collaboration between national registers: the Nordic example , 2018, RMD Open.

[18]  A. Loft,et al.  Validity and completeness of rheumatoid arthritis diagnoses in the nationwide DANBIO clinical register and the Danish National Patient Registry , 2017, Clinical epidemiology.

[19]  P. Isomäki,et al.  Drug survival on tumour necrosis factor inhibitors in patients with rheumatoid arthritis in Finland , 2017, Scandinavian journal of rheumatology.

[20]  H. Stefánsson,et al.  Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations , 2017, npj Genomic Medicine.

[21]  H. Yokozeki,et al.  Infliximab-Induced Aseptic Meningitis during the Treatment of Psoriatic Arthritis , 2017, Case Reports in Dermatology.

[22]  L. Jacobsson,et al.  Are ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events? A prospective nationwide population-based cohort study , 2017, Arthritis Research & Therapy.

[23]  E. Andreadou,et al.  CNS Demyelination with TNF-α Blockers , 2017, Current Neurology and Neuroscience Reports.

[24]  N. Tachibana,et al.  Rheumatoid Meningitis Occurring during Etanercept Treatment , 2017, Case reports in neurological medicine.

[25]  M. Dougados,et al.  2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis , 2017, Annals of the rheumatic diseases.

[26]  M. Hetland,et al.  The Danish nationwide clinical register for patients with rheumatoid arthritis: DANBIO , 2016, Clinical epidemiology.

[27]  A. Steck,et al.  Anti‐TNF alpha medications and neuropathy , 2015, Journal of the peripheral nervous system : JPNS.

[28]  Y. Konttinen,et al.  Rates of Serious Infections and Malignancies Among Patients with Rheumatoid Arthritis Receiving Either Tumor Necrosis Factor Inhibitor or Rituximab Therapy , 2015, The Journal of Rheumatology.

[29]  A. Odén,et al.  High Nationwide Incidence of Multiple Sclerosis in Sweden , 2014, PloS one.

[30]  J. Askling,et al.  The Swedish Rheumatology Quality Register: optimisation of rheumatic disease assessments using register-enriched data. , 2014, Clinical and experimental rheumatology.

[31]  M. Argyropoulou,et al.  Neurological adverse events in patients receiving anti-TNF therapy: a prospective imaging and electrophysiological study , 2014, Arthritis Research & Therapy.

[32]  L. Dreyer,et al.  Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic: description of six cases , 2014, Clinical Rheumatology.

[33]  L. Fugger,et al.  A clinical conundrum: the detrimental effect of TNF antagonists in multiple sclerosis. , 2013, Pharmacogenomics.

[34]  P. Deepak,et al.  Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System , 2013, Alimentary pharmacology & therapeutics.

[35]  D. Szymkowski,et al.  Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. , 2011, Brain : a journal of neurology.

[36]  Takahiko Horiuchi,et al.  Transmembrane TNF-α: structure, function and interaction with anti-TNF agents , 2010, Rheumatology.

[37]  E. Sasso,et al.  Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. , 2009, Clinical immunology.

[38]  Liam Smeeth,et al.  Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? , 2009, American journal of epidemiology.

[39]  T. Kvien,et al.  A Norwegian DMARD register: prescriptions of DMARDs and biological agents to patients with inflammatory rheumatic diseases. , 2005, Clinical and experimental rheumatology.

[40]  Xiao-Yu Song,et al.  Binding and functional comparisons of two types of tumor necrosis factor antagonists. , 2002, The Journal of pharmacology and experimental therapeutics.

[41]  D. Paty,et al.  TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter study , 1999, Neurology.

[42]  F. Barkhof,et al.  Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2 , 1996, Neurology.

[43]  T. Horiuchi,et al.  Molecular mechanisms of action of anti‐TNF‐&agr; agents – Comparison among therapeutic TNF‐&agr; antagonists , 2018, Cytokine.