Effect of n-3 PUFA on extracellular matrix protein turnover in patients with psoriatic arthritis: a randomized, double-blind, placebo-controlled trial

Signe Holm Nielsen, Samra Sardar, Anne Sofie Siebuhr, Annette Schlemmer, Erik Berg Schmidt, Anne-Christine Bay-Jensen, Morten A Karsdal, Jeppe Hagstrup Christensen, Salome Kristensen, Signe Holm Nielsen, Samra Sardar, Anne Sofie Siebuhr, Annette Schlemmer, Erik Berg Schmidt, Anne-Christine Bay-Jensen, Morten A Karsdal, Jeppe Hagstrup Christensen, Salome Kristensen

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by involvement of skin, axial and peripheral skeleton. An altered balance between extracellular matrix (ECM) formation and breakdown is a key event in PsA, and changes in ECM protein metabolites may provide insight to tissue changes. Dietary fish oils (n-3 PUFA) might affect the inflammation driven tissue turnover. The aim was to evaluate ECM metabolites in patients with PsA compared to healthy individuals and investigate the effects of n-3 PUFA. The 24-week randomized, double-blind, placebo-controlled trial of PUFA included 142 patients with PsA. Fifty-seven healthy individuals were included for comparison. This study is a sub-study investigating biomarkers of tissue remodelling as secondary outcomes. Serum samples at baseline and 24 weeks and healthy individuals were obtained, while a panel of ECM metabolites reflecting bone and soft tissue turnover were measured by ELISAs: PRO-C1, PRO-C3, PRO-C4, C1M, C3M, C4M, CTX-I and Osteocalcin (OC). C1M, PRO-C3, PRO-C4 and C4M was found to be elevated in PsA patients compared to the healthy individuals (from 56 to 792%, all p < 0.0001), where no differences were found for OC, CTX-I, PRO-C1 and C3M. PRO-C3 was increased by 7% in patients receiving n-3 PUFA after 24 weeks compared to baseline levels (p = 0.002). None of the other biomarkers was changed with n-3 PUFA treatment. This indicates that tissue turnover is increased in PsA patients compared to healthy individuals, while n-3 PUFA treatment for 24 weeks did not have an effect on tissue turnover. Trial registration NCT01818804. Registered 27 March 2013-Completed 18 February 2016. https://ichgcp.net/clinical-trials-registry/NCT01818804?term=NCT01818804&rank=1.

Keywords: Biomarkers; Collagens; Fish oil; Psoriatic arthritis.

Conflict of interest statement

SHN, ASS, ACBJ and MAK are full-time employees at Nordic Bioscience A/S. Nordic Bioscience is a privately-owned, small–medium size enterprise (SME) partly focused on the development of biomarkers. None of the authors received fees, bonuses or other benefits for the work described in the manuscript. MAK and ACBJ hold stocks in Nordic Bioscience A/S.

Figures

Fig. 1
Fig. 1
Flowchart of the trial
Fig. 2
Fig. 2
Levels of collagen formation and degradation biomarkers in serum from healthy controls (n = 57) and patients with PsA (n = 142). a. Serum levels of formation of collagen type I (PRO-C1), b. Serum levels of degradation of collagen type I (C1M), c. Serum levels of formation of collagen type III (PRO-C3), d. Serum levels of degradation of collagen type III, e. Serum levels of formation of collagen type VI (PRO-C4), b. Serum levels of degradation of collagen type IV (C4M). Statistical differences between the healthy controls and PsA patients were calculated using an unpaired t test for PRO-C3, and LOG10 transformed PRO-C1, C1M, C3M, PRO-C4 and C4M. Significance threshold was set at p < 0.05 and data is presented as Tukey boxplots. Significance levels: ****p < 0.0001
Fig. 3
Fig. 3
Levels of bone formation and degradation biomarkers in serum from healthy controls (n = 6) and patients with PsA (n = 142). a. Serum levels of bone formation measured by osteocalcin (OC) and b. Serum levels of bone degradation measured by CTX-I. Statistical differences between the healthy controls and PsA patients were calculated using an unpaired t test for OC, and LOG10 transformed CTX-I. Data is presented as Tukey boxplots
Fig. 4
Fig. 4
Biomarker levels in placebo (n = 57) and n-3 PUFA (n = 142) treated patients at baseline and 24 weeks. a Serum levels of the bone formation biomarker osteocalcin (OC), b Serum levels of the bone degradation biomarker CTX-I, c Serum levels of the collagen type I biomarker, PRO-C1, d Serum levels of the collagen type III formation biomarker, PRO-C3, e Serum levels of the collagen type IV formation biomarker, PRO-C4, f Serum levels of the collagen type I degradation biomarker, C1M, g Serum levels of the collagen type III degradation biomarker C3M, and h Serum levels of the collagen type IV degradation biomarker, C4M. Statistical differences between the baseline and 24 weeks of follow-up were calculated using a paired t test for OC and PRO-C3, and LOG10 transformed CTX-I PRO-C1, C1M, C3M, PRO-C4 and C4M. Significance threshold was set at p < 0.05 and data is presented as Tukey boxplots. Significance levels: **p < 0.01

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