Glucocorticoid Treatment in Early Rheumatoid Arthritis Is Associated with Increased Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) Levels: A Post-hoc Analysis of a Randomized Controlled Trial (NORD-STAR)

Kristina Lend¹, Jos W.R. Twisk², Nupur Kumar³, John Lampa⁴, Anna Rudin⁵, Merete Hetland⁶, Till Uhlig⁷, Dan Nordstrom⁸, Mikkel Østergaard⁹, Marte Schrumpf Heiberg¹⁰, Espen A Haavardsholm¹⁰, Bjorn Gudbjornsson¹¹, Tuulikki Sokka-Isler¹², Gerdur Maria Grondal¹³, Kim Hørslev-Petersen¹⁴, Michael Nurmohamed², Ronald van Vollenhoven² and Johan Frostegård³, ¹Amsterdam UMC, Karolinska Institute, Stockholm, Sweden, ²Amsterdam University Medical Centers, Amsterdam, Netherlands, ³Karolinska Institutet, Stockholm, Sweden, ⁴Stockholm County, Hãsselby, Sweden, ⁵Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, ⁶Copenhagen Center for Arthritis Research, Rigshospitalet, Copenhagen, Denmark, ⁷Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway, ⁸Helsinki University Hospital, Helsinki, Finland, ⁹Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet; University of Copenhagen, Copenhagen, Denmark, ¹⁰Diakonhjemmet Hospital, Oslo, Norway, ¹¹Centre for Rheumatology Research, University Hospital, Reykjavik, Iceland, ¹²Jyvaskyla Central Hospital, Jyväskylä, Finland, ¹³Department for Rheumatology, Landspitali University Hospital, Reykjavik, Iceland, ¹⁴University of Southern Denmark, Odense, Denmark

Meeting: ACR Convergence 2023

Keywords: Anti-CCP, Cardiovascular, glucocorticoids, rheumatoid arthritis, Rheumatoid Factor

Session Information

Date: Tuesday, November 14, 2023

Title: (2141–2176) RA – Treatments Poster III

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Rheumatoid arthritis (RA) is associated with an elevated risk for developing atherosclerotic cardiovascular disease (CVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism as it gives an increased breakdown of LDL-receptors on the liver resulting in enhanced LDL-cholesterol levels. We aimed to investigate i) the influence of glucocorticoids and biologic treatments on PCSK9 levels and ii) whether the presence of autoantibodies associates with the changes in the PCSK9 levels in DMARD-naïve early RA patients after treatment.

Methods: In this post-hoc analysis of the phase 4 NORD-STAR randomized controlled trial, PCSK9 levels were assessed in 330 Swedish patients who were randomised (1:1:1:1) to receive methotrexate (MTX) in combination with glucocorticoids (GC), certolizumab-pegol (CZP), abatacept (ABA), or tocilizumab (TCZ). PCSK9 levels were determined by commercial ELISA kit (R&D Systems, UK) at baseline and 24 weeks after the initiation of randomised RA treatment. The assay range of ELISA was 125.0–8000 pg/mL. Linear regression models were used to analyse the difference between the treatment groups on PCSK9 levels at 24 weeks. Analyses were adjusted for the baseline level of PCSK9, sex, age, BMI, DAS28-CRP, anti-citrullinated protein antibody (ACPA) status, rheumatoid factor (RF) status, and statin use at 24 weeks. In a second analysis, the interaction between the treatment groups and RF, ACPA and antinuclear antibody (ANA) were added to the model.

Results: Baseline characteristics and the medications of interest are shown in Table 1. The mean PCSK9 levels at baseline were similar across treatment groups. At 24 weeks, highest PCSK9 levels were observed in the MTX+GC treatment group (see table 2). The mean PCSK9 levels at 24 weeks were as follows: MTX+GC (1934 pg/mL [SD 888]); CZP+MTX (1679 [759]); ABA+MTX (1693 [634]); and TCZ+MTX (1784 [761]). Because the effect of the three biological treatment groups on PCSK9 levels at week 24 were more or less the same, for the analyses with the interactions with RF, ACPA and ANA, we combined the three biological treatment groups into one group in order to increase power. At 24 weeks, PCSK9 levels were significantly lower in the pooled biologic treatment group compared with the GC+MTX treatment group(β coefficient -194.9; 95% CI -374.1 to -15.8). Interaction analyses demonstrated that the differences between MTX+GC and biological treatments was most pronounced for RF, ACPA and ANA positive patients (See table 3).

Conclusion: Glucocorticoid treatment was associated with increased PCSK9 levels at 24 weeks. These increases were observed primarily in RF, ACPA, ANA positive patients. Our data provide a potential mechanistic link between glucocorticoid treatment and cardiovascular disease.

Table 1. Baseline characteristics and the medication of interest at baseline and at 24 weeks of patients with early rheumatoid arthritis.

Table 2. Mean levels of PCSK9 at baseline and 24 weeks after the initiation of randomised RA treatment.

Table 3. Results of interaction analysis estimating the influence of autoantibody status on PCSK9 levels between glucocorticoid treatment and pooled biologic treatment at 24 weeks.

Disclosures: K. Lend: None; J. Twisk: None; N. Kumar: None; J. Lampa: None; A. Rudin: AstraZeneca, 12, financial support; M. Hetland: AbbVie/Abbott, 1, 5, Bristol-Myers Squibb(BMS), 5, Danbio, 12, Chari of Danbio registry, Eli Lilly, 5, MEDAC, 6, Novartis, 5, Pfizer, 5, 6, Sandoz, 5, 6; T. Uhlig: Galapagos, 2, 6, Lilly, 2, 6, Novartis, 2, 6, Pfizer, 2, 6, UCB, 2, 6; D. Nordstrom: AbbVie/Abbott, 2, BMS, 2, Lilly, 2, MSD, 2, Novartis, 2, Pfizer, 2, UCB, 2; M. Østergaard: AbbVie, 2, 5, 6, Amgen, 5, Boehringer-Ingelheim, 2, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, Celgene, 2, 5, 6, Eli Lilly, 2, 6, Galapagos, 2, 6, Gilead, 2, 6, Hospira, 2, 6, Janssen, 2, 6, MEDAC, 6, Merck, 2, 5, 6, Novartis, 2, 5, 6, Novo Nordisk, 2, 6, Orion, 2, 6, Pfizer, 2, 6, Regeneron, 2, 6, Roche, 2, 6, Sandoz, 2, 6, Sanofi, 2, 6, UCB, 2, 6; M. Schrumpf Heiberg: Roche, 6; E. Haavardsholm: None; B. Gudbjornsson: Nordic-Pharma, 6, Novartis, 2, 6; T. Sokka-Isler: None; G. Grondal: None; K. Hørslev-Petersen: None; M. Nurmohamed: None; R. van Vollenhoven: AbbVie, 2, 6, AstraZeneca, 2, 5, 6, Biogen, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, Galapagos, 2, 5, 6, GlaxoSmithKline, 6, Janssen, 2, 6, MSD/Merck Sharp and Dohme, 5, Novartis, 5, Pfizer, 2, 5, 6, RemeGen, 2, Roche, 5, Sanofi, 5, UCB, 2, 5, 6; J. Frostegård: None.

To cite this abstract in AMA style:

Lend K, Twisk J, Kumar N, Lampa J, Rudin A, Hetland M, Uhlig T, Nordstrom D, Østergaard M, Schrumpf Heiberg M, Haavardsholm E, Gudbjornsson B, Sokka-Isler T, Grondal G, Hørslev-Petersen K, Nurmohamed M, van Vollenhoven R, Frostegård J. Glucocorticoid Treatment in Early Rheumatoid Arthritis Is Associated with Increased Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) Levels: A Post-hoc Analysis of a Randomized Controlled Trial (NORD-STAR) [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/glucocorticoid-treatment-in-early-rheumatoid-arthritis-is-associated-with-increased-proprotein-convertase-subtilisin-kexin-type-9-pcsk9-levels-a-post-hoc-analysis-of-a-randomized-controlled-trial/. Accessed .

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