Differential glucocorticoid metabolism in patients with persistent versus resolving inflammatory arthritis

Abstract

Introduction: Impairment in the ability of the inflamed synovium to generate cortisol has been proposed to be a factor in the persistence and severity of inflammatory arthritis. In the inflamed synovium, cortisol is generated from cortisone by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. The objective of this study was to determine the role of endogenous glucocorticoid metabolism in the development of persistent inflammatory arthritis.

Methods: Urine samples were collected from patients with early arthritis (symptoms ≤12 weeks duration) whose final diagnostic outcomes were established after clinical follow-up and from patients with established rheumatoid arthritis (RA). All patients were free of disease-modifying anti-rheumatic drugs at the time of sample collection. Systemic measures of glucocorticoid metabolism were assessed in the urine samples by gas chromatography/mass spectrometry. Clinical data including CRP and ESR were also collected at baseline.

Results: Systemic measures of 11β-HSD1 activity were significantly higher in patients with early arthritis whose disease went on to persist, and also in the subgroup of patients with persistent disease who developed RA, when compared with patients whose synovitis resolved over time. We observed a significant positive correlation between systemic 11β-HSD1 activity and ESR/CRP in patients with established RA but not in any of the early arthritis patients group.

Conclusions: The present study demonstrates that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11β-HSD1 activity when compared with patients whose synovitis developed into RA or other forms of persistent arthritis. Low absolute levels of 11β-HSD1 activity do not therefore appear to be a major contributor to the development of RA and it is possible that a high total body 11β-HSD1 activity during early arthritis may reduce the probability of disease resolution.

Figure 1

Differences in systemic measures of GC metabolism in patients with early arthritis and established RA. Systemic measures of 11β-HSD1 activity in patients with early arthritis of different outcomes and established RA: (THF + 5αTHF)/THE ratio (A) and cortols/cortolones ratio (B). UFF/UFE ratio, an indicator of changes in renal 11β-HSD2 activity (C). 5αTHF/THF, a systemic measure of 5α-reductase activity (D). Values for (THF + 5αTHF)/THE ratio, cortols/cortolones ratio and 5αTHF/THF ratio were normally distributed whereas values for UFF/UFE ratio were not normally distributed. Individual values and means are represented on the graph. Comparisons between different outcome groups for normally distributed urine corticosteroid metabolite ratios ((THF + 5αTHF)/THE and cortols/cortolones) were carried out using the unpaired t test. Comparisons between different outcome groups for non-normally distributed urine corticosteroid metabolite ratios (UFF/UFE and 5αTHF/THF) were carried out using the Mann-Whitney test. A P value <0.05 was considered statistically significant. Patients with early resolving arthritis (circles), all patients with early persistent arthritis (squares), early persistent RA (upward triangles) and established RA (downward triangles). 11β-HSD, 11β-hydroxysteroid dehydrogenase type 1; GC, glucocorticoids; RA, rheumatoid arthritis; (THF + 5αTHF)/THE ratio, (tetrahydrocortisol + 5αtetrahydrocorticol)/tetrahydrocortisone ratio; UFF/UFE ratio, urinary-free cortisol/cortisone ratio.

Figure 2

Clinical measures of disease activity in patients with early arthritis and established RA. ESR (A) and CRP (B) levels in patients with early resolving arthritis (circles), all patients with early persistent arthritis (squares), early persistent RA (upward triangles) and established RA (downward triangles). Individual values and medians are represented on the graph. Data for ESR and CRP were not normally distributed; the Mann-Whitney test was used for comparison between the outcome groups. A P value <0.05 was considered statistically significant. ESR, erythrocyte sedimentation rate (mm/hour); CRP, C-reactive protein (mg/L). RA, rheumatoid arthritis.

Figure 3

Correlation of ESR and CRP with global 11β-HSD1 activity in all patients analysed together. Correlation between (THF + 5αTHF)/THE ratio and ESR (A), and CRP (B). Correlation coefficient (rho) and the significance of the correlation (P value) were calculated using Spearman’s correlation. ESR, erythrocyte sedimentation rate (mm/hour); CRP, C-reactive protein (mg/L). 11β-HSD, 11β-hydroxysteroid dehydrogenase type 1; (THF + 5αTHF)/THE ratio, (tetrahydrocortisol + 5αtetrahydrocorticol)/tetrahydrocortisone ratio.

Figure 4

Correlation of ESR and CRP with global 11β-HSD1 activity in patients with early arthritis and established RA analysed individually. Correlation between (THF + 5αTHF)/THE ratios and: ESR in established RA patients (A), CRP in established RA patients (B), ESR in all patients with early persistent arthritis (C), CRP in all patients with early persistent arthritis (D), ESR in early persistent RA patients (E), CRP in early persistent RA patients (F), ESR in early resolving arthritis patients (G) and CRP in early resolving arthritis patients (H). Correlation coefficient (rho) and the significance of the correlation (P value) were calculated using Spearman’s correlation. ESR, erythrocyte sedimentation rate (mm/hour); CRP, C-reactive protein (mg/L). 11β-HSD, 11β-hydroxysteroid dehydrogenase type 1; CRP, C-reactive protein (mg/L); RA, rheumatoid arthritis.

Figure 5

Correlation of ESR and CRP with global 11β-HSD1 activity in patients with early arthritis and established RA analysed individually. Correlation between cortols/cortolones ratio and: ESR in all recruited patients analysed together (A), CRP in all recruited patients analysed together (B), ESR in established RA patients (C), CRP in established RA patients (D), ESR in all patients with early persistent arthritis (E), CRP in all patients with early persistent arthritis (F), ESR in early persistent RA patients (G), CRP in early persistent RA patients (H), ESR in early resolving arthritis patients (I), CRP in early resolving arthritis patients (J). Correlation coefficient (rho) and the significance of the correlation (P value) were calculated using Spearman’s correlation. ESR, erythrocyte sedimentation rate (mm/hour); CRP, C-reactive protein (mg/L). 11β-HSD, 11β-hydroxysteroid dehydrogenase type 1; RA, rheumatoid arthritis.