Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study

Abstract

Objectives: A reduced adrenal reserve-associated cortisol production relative to the enhanced needs of chronic inflammation (disproportion principle) has been observed in rheumatoid arthritis (RA). We examined the possible clinical value of diurnal cortisol measurements in active RA on treatment response prediction.

Methods: Diurnal cortisol production (measured at: 08-12:00/18:00-22:00) was assessed by electrochemiluminescence immunoassay in 28 consecutive patients with moderately/highly active RA, as well as 3 and 6 months after treatment initiation or/escalation. Twenty-eight COVID-19 patients and 28 age-matched healthy individuals (HC) served as controls.

Results: Saliva diurnal cortisol production in patients with RA was similar to that of HC, despite 12-fold higher serum C reactive protein (CRP) levels, and lower than COVID-19 patients (area under the curve: RA: 87.0±37.6 vs COVID-19: 146.7±14.3, p<0.001), having similarly high CRP. Moreover, a disturbed circadian cortisol rhythm at baseline was evident in 15 of 28 of patients with RA vs 4 of 28 and 20 of 28 of HC and COVID-19 patients, respectively. Treatment-induced minimal disease activity (MDA) at 6 months was achieved by 16 of 28 patients. Despite comparable demographics and clinical characteristics at baseline, non-MDA patients had lower baseline morning cortisol and higher adrenocorticotropic hormone (ACTH) levels compared with patients on MDA (cortisol: 10.9±4.0 vs 18.4±8.2 nmol/L, respectively, p=0.005 and ACTH: 4.8±3.3 vs 2.4±0.4 pmol/L, respectively, p=0.047). Baseline morning cortisol <13.9 nmol/L predicted non-MDA at 6 months (75% sensitivity, 92% specificity, p=0.006). Prospective measurements revealed that individualised diurnal cortisol production remained largely unchanged from baseline to 3 and 6 months.

Conclusions: An impaired adrenal reserve is present in patients with RA. Further studies to confirm that assessment of diurnal cortisol production may be useful in guiding treatment decisions and/or predicting treatment response in RA are warranted.

Trial registration number: NCT05671627.

Keywords: Arthritis; Arthritis, Rheumatoid; Glucocorticoids.

Figure 1

Diurnal saliva cortisol levels (A), time-integrated daily saliva cortisol production (B) and serum CRP levels (C) at baseline in patients with RA, COVID-19 patients and healthy controls (HC). Saliva cortisol levels were measured at 08:00, 12:00, 18:00 and 22:00, and the time-integrated daily saliva cortisol production was calculated as the total area under the curve (AUC). Lines in (A) represent mean±SEM, and in (B) and (C) represent mean±SD. P values are derived from one-way ANOVA followed by Bonferroni multiple comparisons test or the non-parametric Kruskal-Wallis followed by Dunn’s multiple comparisons test for measurements that did not follow a normal distribution (saliva cortisol measurements did not follow a normal distribution). *P<0.05 compared with controls; #p<0.05 compared with patients with RA. ANOVA, analysis of variance; CRP, C reactive protein; RA, rheumatoid arthritis.

Figure 2

Receiver operating characteristic curve for baseline morning saliva cortisol levels predicting no minimal disease activity (DAS >2.85) at 6 months in patients with RA. AUC: 0.807, 95% CI: 0.634 to 0.981, p=0.006. AUC, area under the curve; DAS, Disease Activity Score; RA, rheumatoid arthritis.