Tumor necrosis factor inhibitors are associated with reduced complement activation in spondylarthropathies: An observational study.

Ingrid Hokstad, Gia Deyab, Morten Wang Fagerland, Torstein Lyberg, Gunnbjørg Hjeltnes, Øystein Førre, Stefan Agewall, Tom Eirik Mollnes, Ivana Hollan

Journal: PloS one 2020;14(7):e0220079

PMID: 31335881

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Abstract

BACKGROUND

The complement system is involved in pathogenesis of cardiovascular disease, and might play a role in accelerated atherogenesis in spondylarthropathies (SpA). Hence, we examined complement activation in SpA, and its relationship to antirheumatic treatment, inflammatory and cardiovascular markers.

METHODS

From PSARA, a prospective observational study, we examined 51 SpA patients (31 psoriatic arthritis (PsA), and 20 ankylosing spondylitis (AS)), starting tumor necrosis factor (TNF) inhibitor alone (n = 25), combined with methotrexate (MTX) (n = 10), or MTX monotherapy (n = 16). Complement activation was determined by the soluble terminal complement complex (sC5b-9), inflammation by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and endothelial function by finger plethysmography (Endopat) at baseline, after 6 weeks and 6 months of treatment.

RESULTS

SpA patients had sC5b-9 levels at (PsA) or above (AS) the upper limit of the estimated reference range. Median sC5b-9 levels decreased significantly from baseline to 6 weeks, with no significant difference between the AS and PsA group. Notably, a significant reduction in sC5b-9 was observed after administration of TNF inhibitor ± MTX, whereas no significant changes were observed in patients treated with MTX alone. Between 6 weeks and 6 months, sC5b-9 remained stable across all subgroups. Reduction in sC5b-9 was independently related to decreased ESR and CRP, and to increased high density cholesterol and total cholesterol. Reduction in sC5b-9 from baseline to 6 weeks was associated with improved EF in age and gender adjusted analyses.

CONCLUSION

TNF-inhibition, but not MTX monotherapy, led to rapid and sustained reduction of complement activation in SpA. Thus, the observed decrease in cardiovascular morbidity in patients treated with TNF-inhibitors might be partly due to its beneficial effect on complement.

TRIAL REGISTRATION

Clinical Trials (NCT00902005), retrospectively registered on the 14th of May 2009.

Address: Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.; Institute of Clinical Sciences, University of Oslo, Oslo, Norway.; Department of Medical Biochemistry, Innlandet Hospital Trust, Lillehammer, Norway.; Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway.; Department of Medical Biochemistry, Oslo University Hospital Ullevål, Oslo, Norway.; Department of Medicine, Innlandet Hospital Trust, Lillehammer, Norway.; Department of Rheumatology, Oslo University Hospital, University of Oslo, Oslo, Norway.; Oslo University Hospital Ullevål, Oslo, Norway.; Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway.; Research Laboratory, Nordland Hospital, Bodø, Norway.; Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.

DOI: 10.1371/journal.pone.0220079

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https://clinicaltrials.gov/search?term=AREA%5BRefe...

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https://assays.cancer.gov/CPTAC-1478

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https://antibodies.cancer.gov/detail/CPTC-CRP-1

MeSH Terms: Adult, Complement Activation, Complement Membrane Attack Complex, Female, Humans, Male, Methotrexate, Middle Aged, Spondylarthropathies, Tumor Necrosis Factor Inhibitors