An Impaired Functional Reserve of Adrenal Cortex May Associate With difficult-to Treat RA: Can a Disturbed Cortisol Circadian Rhythm Serve as a Predictor of Difficult-to-treat RA?

The European League Against Rheumatism (EULAR), acknowledging the critical issue of the complications, of long term treatment with glucocorticoids in the most recent update of the management guidelines for Rheumatoid arthritis, recommends tapering (on sustained clinical remission) of oral glucocorticoids treatment at the earliest feasible time point of therapeutic course and to the lowest daily dose, preferably <7.5mg/day (prednisone equivalent), until the final target of withdrawal is succeeded. In clinical practice, these guidelines are often difficult to follow due to the high risk of disease flares after tapering or stopping glucocorticoids administration. This inability of tapering oral glucocorticoids below 7.5mg/day of prednisone or an equivalent synthetic glucocorticoid is included in the recent definition of difficult-to-treat Rheumatoid arthritis. SΕΜΙRΑ (Steroid EliMination In Rheumatoid Arthritis) study, a double-blind, multicentre, randomised controlled trial, compared oral glucocorticoids tapering with the continuation of low dose oral glucocorticoids. The population study consisted of 259 RA patients with low disease activity on treatment with 5mg per day prednisone and tocilizumab, an anti-interleukin (IL)-6 receptor antibody. The study demonstrated that the continued-prednisone regimen provided better maintenance of disease remission than did the tapered-prednisone regimen for the study period of 24 weeks with no symptoms suggestive of AI. However, the study protocol did not include biochemical assessment of adrenocortical function.

Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in Rheumatoid arthritis. Although the underlying molecular mechanisms remain unknown, both chronic overexpression of proinflammatory cytokines and chronic stress may contribute in the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis and the target tissue glucocorticoid resistance that have been described, but not systematically studied. Thus, a precise longitudinal assessment of endogenous cortisol production may be needed for optimal management of patients with Rheumatoid arthritis. Based on the above, the investigators seek to investigate the hypothesis that an impaired functional reserve of adrenal cortex, due to chronic over-expression of pro-inflammatory cytokines and/or chronic stress may contribute to the development of Rheumatoid arthritis and/or associate with difficult-to treat RA. If this is the case, then a disturbed cortisol circadian rhythm reflecting this impairment may serve as a predictor of difficult-to-treat RA during the first diagnosis. In order to address this issue, the investigators designed a prospective cohort study including adult patients with Rheumatoid arthritis who require drug treatment for the first time or escalation of existing treatment due to active disease. Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens when started will not exceed 15 mg/day, and will be given for at least 3 months), following EULAR recommendations for RA treatment.

Patients will be monitored at baseline, 3 months, 6 months and 12 months, assessing disease response to treatment, the need for continuing glucocorticoid treatment, inflammatory indexes, and diurnal salivary cortisol levels. Patients' classification will be based on EULAR response to treatment criteria for RA and cortisol circadian rhythm will be comparatively assessed (at baseline and at 3/6/12 months) between groups based on treatment response (EULAR guidelines).