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

Abstract

Background: 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. Methods: 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.Results: 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. Conclusion: 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.

Chronobiology and Chronotherapy in Inflammatory Joint Diseases

“…In a prospective observational study, Benucci et al [100] evaluated changes in inflammatory markers and their correlation with IR or MR 6-methylprednisolone (6-MP) in patients with early PMR. The results showed significant differences between baseline and end-of-treatment values in serum levels of IL-6 and CRP in patients treated with the MR regimen and in serum cortisol levels in the patients treated with 6-MP [86]. In addition, during the first month of treatment, there was a significant decrease in IL-6 levels: 76.7% of the patients treated with MR-P had IL-6 levels at or below the upper normal limit, whereas 52.6% of those treated with 6-MP had normal IL6 levels [100].…”

“…Overall, low-dose MR prednisone seems to be able to improve the disease course, reduce morning stiffness and morning serum levels of IL-6, and induce a significantly higher percentage of improvement of the American College of Rheumatology response criteria ACR20 and ACR50 in combination with DMARDs compared to DMARD monotherapy [84]. One concern regarding the use of GCs is that, although powerful and widely used [85], they are frequently associated with multiple adverse effects (AEs), including bone loss, diabetes, and suppression of the HPA axis, which leads to adrenocortical hypotrophy and iatrogenic adrenal insufficiency [86]. No clinically evident AEs indicating aggravated HPA axis suppression were observed in the CAPRA trials [81,82], but to examine possible AEs of MR prednisone on the HPA axis, a small sub-study within CAPRA-1 was undertaken [80,87].…”

Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID

“…We suggest that Long COVID, as well as other post-viral infection sickness syndromes or sickness syndromes associated with chronic inflammatory diseases in predisposed individuals [ 25 , 26 ], are characterized by suppressed responsiveness of the HPA axis. The protracted subsequent lack of axis recovery due to a post-illness state of hypocortisolism in these individuals may be the underlying pathophysiologic mechanism responsible for, at least, some of sickness syndrome manifestations and the immune perturbations seen in Long COVID ( Fig.…”

“…Why some people are more prone to develop Long COVID, and whether HPA axis stimulants or exogenously administered glucocorticoids could have a role in the management of some of these individuals, warrant further investigation. Predisposed individuals may be those with an intrinsically compromised adrenal reserve that fails to compensate for intense or long standing increased stress [ 26 ], as seen in patients with immune-mediated and inflammatory diseases, such as rheumatoid arthritis [ 25 , 26 ].…”

COVID-19 vaccination: a possible trigger for Addisonian crisis in a patient with Addison’s disease

“…8,14 Other causes of primary AI include: infectious (e.g., tuberculosis, AIDS, syphilis), bilateral adrenal metastases, bilateral adrenal haemorrhage (e.g., 'Waterhouse-Friderichsen syndrome' associated with meningococcal sepsis), bilateral adrenal infiltration (e.g., amyloidosis, hemochromatosis), bilateral adrenalectomy, drug-induced or iatrogenic (heparin, warfarin, sunitinib, fluconazole, phenytoin, rifampicin, long term glucocorticoid use e.g., for the treatment of rheumatoid arthritis), genetic or neonatal (congenital adrenal hyperplasia, adrenal hypoplasia congenita, infantile Refsum disease, cholesterol synthesis disorders, etc). 8,13,15,16 Autoimmune Addison's disease (primary AI) is thought to be caused by destruction of the adrenal cortex by Tcell (CD4 + & CD8 + ) mediated immune responses, with assistance from macrophages and dendritic cells. 10,12,13,15 The mechanism of autoantibody creation is described as being usually aimed towards the 21-hydroxylase enzyme (the autoantigen).…”