IntroductionTocilizumab (TCZ) treatment is associated with dyslipidaemia, including a rise in triglycerides through a mechanism poorly understood. Three molecules play key roles in the regulation of triglyceride metabolism: apolipoprotein C‐III (ApoC‐III), angiopoietin‐like protein 4(ANGPLT4) and lipoprotein lipase (LPL). The aim of this work was to analyse whether the changes in triglycerides shown by TCZ‐treated RA patients could stem from the dysregulation that can occur in these regulatory molecules.MethodsTwenty‐seven RA patients included in the TOCRIVAR study who received TCZ (8 mg/kg IV/q4w) were evaluated at baseline and at Weeks 12, 24 and 52 of treatment. ANGPTL4, ApoC‐III and LPL, a complete lipid profile and RA disease activity, were analysed at baseline and at each visit. Multivariable linear mixed models were performed to study changes over time in lipids and regulatory molecules.ResultsAfter 24 weeks of TCZ treatment, HDL cholesterol, apolipoprotein A1 and triglycerides increased, whereas lipoprotein (a) decreased significantly from baseline values. However, 1 year after TCZ, no significant differences in lipid pattern were observed with respect to baseline. Serum ANGPTL4 and Apo‐CIII levels decreased gradually over time, both being significantly lower than baseline values at Week 52. LPL concentration did not change significantly during TCZ treatment. Remarkably, the elevation of triglycerides at Week 24 maintained its statistical significance after adjusting for the changes in ApoC‐III, ANGPTL4 and LPL.ConclusionIn TCZ‐treated RA patients basal serum levels of ANGPLT4 and ApoC‐III, but not LPL, decreased significantly. However, the elevation of triglycerides after TCZ was not related to changes in these regulatory molecules.

BackgroundTocilizumab is a humanized immunoglobulin G antibody to the interleukin 6 (IL-6) receptor that is used in the treatment of patients with rheumatoid arthritis (RA). Patients receiving TCZ are more likely to experience an elevation in total cholesterol, triglycerides and the ratio of low-density lipoprotein to high-density lipoprotein cholesterol. Elevated triglycerides or triglyceride-rich lipoproteins are cause of cardiovascular disease. Although the pathways for the synthesis and metabolism of triglycerides are complex and diverse, three molecules play a central role in their metabolism: apolipoprotein C-III (ApoC3), angiopoietin-like protein 4 (ANGPLT4), and lipoprotein lipase (LPL). LPL hydrolyzes the triglycerides core of chylomicronsand has a crucial role in regulating plasma triglycerides levels. Besides, ApoC3 and ANGPLT4 participates in the regulation of triglycerides metabolism by the inhibition of LPL, thereby also decreasing the lipolysis of circulating triglycerides.ObjectivesThe objective of this study was to evaluate the influence that TCZ has on the TG metabolism axis constituted by ANGPTL4, ApoC3 and LPL. In a second step we have assessed whether the changes that TCZ exerts on the lipid profile can be justified by a modification of this axis.MethodsTOCRIVAR (ClinicalTrials.gov:NCT01752335) is a one-year prospective clinical trial that analyzes the influence of TCZ on different cardiovascular risk factors including lipid pattern. Twenty-seven RA patients receiving TCZ (8 mg/kg IV/q4w) were assessed at baseline and weeks 12, 24, and 52. Disease activity indexes, serum levels of ApoC3, ANGPLT4 and LPL, and lipoproteins serum concentrations were assessed at every visit.ResultsAcute phase reactants and disease activity were significantly reduced during study visits and at the end of treatment after one year with TCZ. While total and LDL cholesterol initially increased in plasma concentration, then decreased to baseline, lipoprotein (a) was significantly lower, and HDL higher, than baseline at all study visits. TG showed a trend to be significantly higher at 6 months (net increase 29 (95%CI -45-68) mg/dl, percentage increase 36 (95%CI -27-52) %, p=0.079). However, TG did not show significant differences at any visit compared to baseline levels. ANGPLT4 (baseline 387 ± 203 vs final 257 ± 32 wk52 ng/ml, p=0.016) and ApoC3 (baseline 10.1 ± 6.7 vs final 6.3 ± 3.7 mg/dl, p=0.023) were significantly lower at the end of the study (week 52) compared to their initial concentrations. LPL also showed a gradual decrease at each visit (baseline 345 ± 289 vs. final 291 ± 197 ng/ml, p=0.57), although statistical significance was not reached (trend test p=0.56). The decrease in DAS28-ESR at each visit was not associated with the changes produced in the three molecules, thus showing that the decrease in the TG metabolism axis does not depend on the lower activity of the disease produced by TCZ. In contrast, the decline in ApoC3 was significantly correlated with the increase in TG at month 3 (Pearson r -0.494, p=0.037) but not at 6 and 12 months.ConclusionTCZ decreases serum levels of ANGPTL4, ApoC3 and LPL. At 3 months, the increase that occurs in TG seems to depend on the inhibition that TCZ exerts over ApoC3. Our findings suggest that the effect of TCZ on the lipid profile in patients with RA could be mediated by the modification that this drug exerts on the ANGPTL4-ApoC3-LPL axis.References[1]Iván Ferraz-Amaro, María Vanesa Hernández-Hernández, Beatriz Tejera-Segura Esmeralda Delgado-Frías, María Macía-Díaz, Jose David Machado, Federico Diaz-González. Effect of IL-6 Receptor Blockade on Proprotein Convertase Subtilisin/Kexin Type-9 and Cholesterol Efflux Capacity in Rheumatoid Arthritis Patients. Horm Metab Res 2019;51(3):200-209.Disclosure of InterestsSergio Santos-Concepción: None declared, Javier Castro-Hernández: None declared, Vanessa Hernández-Hernández: None declared, Cristina Luna-Gomez: None declared, Iván Ferraz-Amaro Speakers bureau: Dr. Iván Ferraz-Amaro and Dr. Diaz-González would like to acknowledge that he has received grants/research supports from Abbott, MSD, Jansen and Roche, as well as consultation fees from company sponsored speakers’ bureaus associated with Abbott, Pfizer, Roche, Sanofi, Celgene, Grant/research support from: Dr. Iván Ferraz-Amaro and Dr. Diaz-González would like to acknowledge that he has received grants/research supports from Abbott, MSD, Jansen and Roche, as well as consultation fees from company sponsored speakers’ bureaus associated with Abbott, Pfizer, Roche, Sanofi, Celgene, Federico Diaz-Gonzalez Speakers bureau: Dr. Iván Ferraz-Amaro and Dr. Diaz-González would like to acknowledge that he has received grants/research supports from Abbott, MSD, Jansen and Roche, as well as consultation fees from company sponsored speakers’ bureaus associated with Abbott, Pfizer, Roche, Sanofi, Celgene, Consultant of: Dr. Iván Ferraz-Amaro and Dr. Diaz-González would like to acknowledge that he has received grants/research supports from Abbott, MSD, Jansen and Roche, as well as consultation fees from company sponsored speakers’ bureaus associated with Abbott, Pfizer, Roche, Sanofi, Celgene