Adrenocortical dysfunction in rheumatoid arthritis: Α narrative review and future directions

Iatrogenic adrenal insufficiency (AI) secondary to long-term treatment with exogenous glucocorticoids (GC) is common in patients with systematic rheumatic diseases, including rheumatoid arthritis (RA). Moreover, a proportion of these patients is always in need of even small doses of glucocorticoids to maintain clinical remission, despite concomitant treatment with conventional and biologic disease-modifying drugs.

We conducted a literature review up to December 2020 on (a) the incidence of AI in both long-term GC-treated and GC-treatment naïve RA patients; (b) the potential effects of increased levels of circulating proinflammatory cytokines, as well as of chronic stress, in adrenocortical function in RA; (c) the circadian cortisol rhythm in RA; and (d) established and evolving methods of assessment of adrenocortical function.

Up to 48% of RA patients develop glucocorticoid-induced AI; however, predictors are not established, while adrenocortical dysfunction may also occur in GC-treatment naïve RA patients. 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 RA. Although the underlying mechanisms are unknown, both proinflammatory cytokines and chronic stress may contribute the most in the adrenals hyporesponsiveness and the target tissue glucocorticoid resistance that have been described, but not systematically studied. A precise longitudinal assessment of endogenous cortisol production may be needed for optimal RA management.

Apart from iatrogenic AI, an intrinsically compromised adrenal reserve in RA may have a pathogenetic role and interfere with effective management, thus deserving further research.