4β‐Hydroxycholesterol Level in Patients With Rheumatoid Arthritis Before vs. After Initiation of bDMARDs and Correlation With Inflammatory State

Abstract

Systemic inflammation has been linked to suppressed CYP3A(4) activity. We determined 4β‐hydroxycholesterol (4βOHC), an endogenous CYP3A4 metabolite, in patients with rheumatoid arthritis (RA) before and after treatment with biological disease‐modifying antirheumatic drugs (bDMARDs). The 4βOHC was compared in 41 patients before and 2–5 months after initiating TNFα inhibitors (n = 31), IL‐6 inhibitors (n = 5), or B‐cell inhibitors (n = 5). Correlations between 4βOHC and inflammatory markers (C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) were also tested before and after bDMARDs. 4βOHC did not differ following bDMARD treatment (P = 0.6), nor in patients who started with IL‐6 inhibitors (median 51.6 vs. 50.6 nmol/L). The 4βOHC and CRP/ESR did not correlate before treatment (P > 0.5), but correlated significantly after bDMARDs (CRP = Spearman r ‐0.40; P < 0.01; ESR = r ‐0.34; P = 0.028) suggesting that mainly non‐CYP3A4‐suppressive cytokines were reduced during treatment. Thus, this study does not support a generally regained CYP3A4 phenotype in patients with RA following initiation of bDMARDs.

Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis

“…RA patients (n = 31) starting treatment with TNF-a inhibitors were included from the Norwegian disease-modifying antirheumatic drug study (ClinicalTrials.gov; identifier NCT01581294). The study protocol, which was previously described in detail (Wollmann et al, 2017), included serum samples collected at baseline (before start of TNF-a inhibitor treatment) and after 3 months of treatment. In the present study, these samples were used for analysis of cytokines, 4bOHC, and total cholesterol.…”

“…The concentration data of 4bOHC applied in the present investigation was also included in a recent investigation (Wollmann et al, 2017), where patients treated with TNF-a inhibitors comprised the major subgroup. In this follow-up project, additional concentration measurements of cholesterol, the precursor of 4bOHC, and analyses of a range of different cytokines were performed in the same serum samples.…”

“…Baseline characteristics of the 31 patients with RA are given. The same patients were also included in a previously published paper (Wollmann et al, 2017).…”

“…with healthy controls, both before and after initiation of biologic diseasemodifying antirheumatic drugs (Wollmann et al, 2017). To obtain knowledge on inflammatory mediators possibly supressing CYP3A4 metabolism in RA patients, the aim of this pilot study was to investigate the associations between serum levels of 4bOHC and cytokines representing different immune responses in patients treated with TNF-a inhibitors in a real-life clinical setting.…”

4β‐Hydroxycholesterol as an Endogenous Biomarker for CYP3A Activity: Literature Review and Critical Evaluation

“…Patients with rheumatoid arthritis have been shown to have reduced CYP3A activity due to downregulation of this enzyme by inflammatory cytokines including tumor necrosis factor α, interleukin (IL)1β, interferon γ, and most importantly IL6 . In a recent study 4β‐OHC concentrations were measured in 41 rheumatoid arthritis patients to assess CYP3A phenotype before and 2–5 months after starting therapy with biological disease‐modifying antirheumatic drugs (bDMARDs) . Treatment with bDMARDs was hypothesized to result in regained CYP3A phenotype as measured by 4β‐OHC.…”