Background/Purpose: Rheumatoid arthritis (RA) has been acknowledged to increase cardiovascular mortality probably due, in part, to a lipid profile different from that observed in the general population. Tocilizumab (TCZ), is associated with increased lipid levels in the context of decreased levels of inflammatory markers. The mechanisms by which TCZ increases lipids are not yet fully understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation, linked to cardiovascular risk. The purpose of the present study was to examine whether PCSK9 serum levels are related to the abnormalities in the lipid profile that TCZ causes in RA patients.

Methods: The prospective TOCRIVAR study (Clin Trial.gov identifier: NTC01752335) analyzes the influence of TCZ on different cardiovascular risk factors in RA patients. Patients received TCZ 8 mg/kg IV q4w for 52 weeks. None of the patients was under statins treatment. Available serum samples were analyzed at baseline and at weeks 12, 24 and 52. PCSK9, lipoproteins serum concentrations and standard lipid profiles were assessed at every visit. Dual-x-ray-absorptiometry-derived body composition (DEXA) and abdominal adiposity by magnetic resonance imaging, were assessed at basal visits and at the end of the study. Cox-regression analysis was performed to study the influence of TCZ over PCSK9 serum levels and lipid profile, adjusting for body composition and PA.

Results: 26 RA patients, 2 males and 24 females, 52±2 years old, were included in the study. Median PCR (Δ-5.3[-0.2–14.8] mg/dl, p=0.00) and DAS28 (Δ-1.8[-1.5–2.2] p=0.00) were markedly reduced within the first 12 weeks and they remained significantly lower compared to basal visit levels throughout the one year of TCZ treatment. Average total cholesterol, HDL-C, and apolipoprotein A and B levels increased after 3 and 6 months of treatment; however, no statistical significant difference were observed, in these values, between the final visit at 12 months and the basal visit. In contrast, lipoprotein A serum concentration decreased after 6 months of TCZ treatment (Δ-3[-2–12] mg/dl, p=0.03). No changes were observed in triglycerides. PCSK9 basal serum concentration was not modified by TCZ treatment and did not differ respect to each visit (mean differences after 3, 6 and 12 months were, 72[-59-241], 67[-133-147] and 90[-252-137] CI95% ng/ml, respectively). Subcutaneous abdominal fat tissue was inferior after one year of treatment (Δ-1766[-6555–450] cm2, p=0.02); however, visceral abdominal fat tissue (p=0.99), VAAT/SAAT ratios (p=0.72) and the percentage of trunk fat (DEXA) (p =0.26) were not influenced by TCZ treatments.

Conclusion: TCZ-induced changes in the lipid profiles of RA patients are not related to degradation of the low-density lipoprotein receptor mediated by PCSK9. One year of treatment with TCZ does not seem to influence body composition adiposity of RA patients, two elements related with lipid profiles. Interestingly, TCZ treatment causes a marked reduction of lipoprotein a plasma concentration, an independent cardiovascular risk factor.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-interleukin-6-receptor-blockade-on-proprotein-convertase-subtilisinkexin-type-9-serum-levels-in-rheumatoid-arthritis-patients/