Simultaneous evaluation of in vivo glucocorticoid sensitivity and expression of glucocorticoid receptor alpha-isoform in rheumatoid arthritis patients

Abstract

Objectives: To analyze glucocorticoid (GC) sensitivity using intravenous very low dose dexamethasone suppression test (IV-VLD-DST) in patients with rheumatoid arthritis (RA) and its correlation with glucocorticoid receptor alpha-isoform (GRα) gene expression. Methods: We evaluated 20 healthy controls and 32 RA patients with Health Assessment Questionnaire (HAQ) and Disease Activity Score 28 joints (DAS) scores and IV-VLD-DST and GRα expression in mononuclear cells. Results: Basal cortisol and the percentage of cortisol reduction after IV-VLD-DST were lower in RA patients than in controls, whereas GRα expression was similar among groups. In the RA group there was an inverse correlation between GRα expression and the percentage of cortisol suppression that was not observed in controls. There was a direct relationship between DAS and GRα expression. Conclusions: Mechanisms involved in GC resistance observed in patients with RA are possibly not at the level of GRα gene expression, since it was similar among groups and GRα increased with disease activity. Arq Bras endocrinol metab. 2009;53(1):24-30. KeywordsGlucocorticoid receptors; rheumatoid arthritis; dexamethasone suppression test resuMo Objetivos: Determinar a sensibilidade aos glicocorticóides (GC) utilizando teste de supressão com dexametasona em doses muito baixas (IV-VLD-DST) em pacientes com artrite reumatóide (AR) e sua correlação com a expressão gênica da isoforma alfa do receptor glicocorticóide (GRα). Métodos: Foram avaliados 20 controles saudáveis e 32 pacientes com AR com Health Assessment Questionnaire (HAQ) e Disease Activity Score 28 joints (DAS), IV-VLD-DST e expressão do GRα em células mononucleares. Resultados: Cortisol basal e porcentagem de redução do cortisol após IV-VLD-DST foram menores no grupo AR do que nos controles, enquanto a expressão de GRα foi similar entre eles. No grupo com AR, ocorreu correlação negativa entre a expressão do GRα e a porcentagem de supressão do cortisol, enquanto nos controles não houve correlação. Ocorreu relação direta entre DAS e expressão de GRα. Conclusões: Sugerimos que os mecanismos envolvidos na resistência aos GC observada na AR não estejam ao nível da expressão gênica do GRα, já que esta é igual entre os grupos e aumenta com a gravidade da doença. It is characterized by synovial membrane inflammation due to proliferation and infiltration of lymphocytes that determine progressive destruction of cartilage and subchondral bone (1,2). Transcription factors, such as activator protein (AP)-1 and nuclear factor kappa-B (NF-κB), determine greater expression of pro-inflammatory cytokines, COX-2, growth factors, acute phase proteins and adhesion molecules (3-6). The expression of NF-κB is increased in RA and seems to be one of the main factors involved in the pathogenesis of the disease (7,8).Glucocorticoids (GCs) activate the cytosolic glucocorticoid receptor (GR), which translocates to the nucleus to regulate target-gene transcription and determines the reduction of synthesis and release of pro-inflamma...

Quantitation of glucocorticoid receptor alpha and NF-κB pathway mRNA and its correlation with disease activity in rheumatoid arthritis patients

“…Glucocorticoid sensitivity in vivo was similar in patients and controls, as assessed by suppression of cortisol after VLD IV-DST, contrary to previous studies (Onda et al, 2004;Cobra et al, 2009). There was no correlation of cortisol suppression with disease activity assessed by DAS28, which should be evaluated in conjunction with clinical findings to allow comparisons.…”

“…Like other studies (Onda et al, 2004;Cobra et al, 2009), we found no difference in the GRα expression in peripheral blood lymphocytes between RA and control groups. There was also no correlation between GRα expression and cortisol suppression after VLD IV-DST in patients or controls.…”

“…There was also no correlation between GRα expression and cortisol suppression after VLD IV-DST in patients or controls. Although there was a weak negative correlation between these variables in patients with RA in the previous study conducted by our group (Cobra et al, 2009), there was also no correlation between these variables in the controls. The difference in these results can be explained again by the difficulty of GC removal in the first study or differences in disease severity.…”

“…There was no correlation of cortisol suppression with disease activity assessed by DAS28, which should be evaluated in conjunction with clinical findings to allow comparisons. Comparing the clinical profile of patients in our previous and current studies, we note that despite being similar with respect to DAS28 values (4.49 and 4.45, respectively), a higher proportion of patients in the first study (Cobra et al, 2009) used 3 or more DMARDs (53.1 vs 14.3%), had higher HAQ score (1.7 vs 0.67), and showed a significant worsening of RA symptoms 60 days after GC discontinuation. We also observed that almost all of those patients resumed the use of GC as part of their regimen in a few months.…”

“…A previous study by our group (Cobra et al, 2009) suggested that the mechanisms involved in resistance to glucocorticoids (GC) observed in RA are not at the glucocorticoid receptor alpha (GRα) mRNA expression level but at the post-receptor level, since increased GRα expression was not sufficient to reduce the inflammatory activity of the disease estimated by the Disease Activity Score 28 (DAS28). RA patients showed increased GRα mRNA expression but decreased dexamethasone suppression capability at the pituitary level.…”