The role of lymphotoxin-α in rheumatoid arthritis
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The role of tumor necrosis factor (TNF) in the inflammatory response in rheumatoid arthritis (RA) is well established, whereas less is known about the role of TNF’s close homolog, lymphotoxin alpha (LTα).
Increased levels of LTα are found in the serum and synovial tissue of patients with RA, and in vitro studies found that LTα-induced proliferation of RA fibroblast-like synoviocytes was at a similar level to TNF. These findings support the idea that anti-LTα treatment could be beneficial in patients with RA, but pateclizumab, an anti-LTα antibody, was not as efficacious as the anti-TNF agent adalimumab in reducing symptoms of RA in a head-to-head study, suggesting that anti-LTα therapies might not represent a valid alternative treatment option in patients with RA. However, suppression of LTα activity might be relevant in the context of RA-related comorbidities, as patients with RA have an increased risk of myocardial infarction (MI) compared with the general population, and specific polymorphisms of the LTα gene have been linked to increased MI risk.
In this review, we summarize the key characteristics of LTα and the most recent findings on the role of LTα in RA.
KeywordsLymphotoxin alpha Tumor necrosis factor Rheumatoid arthritis Pateclizumab Etanercept
Medical writing support was provided by Helen Jones and Sabrina Giavara of Engage Scientific Solutions and was funded by Pfizer.
Compliance with ethical standards
Conflict of interest
TH and YF are employees of Pfizer Japan Inc. TH is a stockholder of Pfizer. KN has received research funding from AbbVie, Astellas, Chugai, Eisai, Mitsubishi-Tanabe, and Ono, and honoraria from Astellas, Ayumi, Chugai, Mitsubishi-Tanabe, Pfizer, and Bristol-Myers Squibb/Ono. AT has no competing interests.
- 5.Manicourt DH, Triki R, Fukuda K, Devogelaer JP, Nagant de Deuxchaisnes C, Thonar EJ. Levels of circulating tumor necrosis factor alpha and interleukin-6 in patients with rheumatoid arthritis. Relationship to serum levels of hyaluronan and antigenic keratan sulfate. Arthritis Rheum. 1993;36:490–9.CrossRefPubMedGoogle Scholar
- 35.Emu B, Luca D, Offutt C, Grogan JL, Rojkovich B, Williams MB, et al. Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin alpha: results of a phase I randomized, placebo-controlled trial. Arthritis Res Ther. 2012;14:R6.CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Kennedy WP, Simon JA, Offutt C, Horn P, Herman A, Townsend MJ, et al. Efficacy and safety of pateclizumab (anti-lymphotoxin-alpha) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study). Arthritis Res Ther. 2014;16:467.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.electronic Medicines Compendium (eMC). Enbrel 25 mg and 50 mg solution for injection in pre-filled pen. 2016. https://www.medicines.org.uk/emc/medicine/22143. Accessed 20 Nov 2017.
- 42.Anolik JH, Ravikumar R, Barnard J, Owen T, Almudevar A, Milner EC, et al. Cutting edge: anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effects on lymphoid germinal centers and follicular dendritic cell networks. J Immunol. 2008;180:688–92.CrossRefPubMedGoogle Scholar
- 50.Low ASL, Symmons DPM, Lunt M, Mercer LK, Gale CP, Watson KD, et al. Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76:654–60.CrossRefPubMedPubMedCentralGoogle Scholar