Glucocorticoids and chronotherapy in rheumatoid arthritis

Maurizio Cutolo, Maurizio Cutolo

Abstract

It is evident that the morning symptoms of rheumatoid arthritis (RA) are linked to the circadian abnormal increase in night inflammation, favoured by inadequate cortisol secretion under conditions of active disease. Therefore, exogenous glucocorticoid treatment is recommended in RA at low doses since it may partially act like a 'replacement therapy'. The prevention/treatment of the night upregulation of the immune/inflammatory reaction (and related flare of cytokine synthesis) has been shown to be more effective when exogenous glucocorticoid administration is obtained with a night-time-release formulation. Large-scale trials documented that modified-release prednisone has greater efficacy then morning prednisone for long-term low-dose glucocorticoid treatment in patients with RA, showing at least a more significant reduction in morning joint stiffness. Interestingly, despite a considerably higher cost than conventional prednisone, chronotherapy with night-time-release prednisone was recognised as a cost-effective option for patients with RA not on glucocorticoids who are eligible for therapy with biological disease-modifying antirheumatic drugs (DMARDs). Moreover, since different cell populations involved in the inflammatory process are particularly activated during the night, other therapeutical approaches used in RA, for example, conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs), should follow the same concepts of glucocorticoid chronotherapy. Indeed, bedtime methotrexate chronotherapy was found to improve RA symptoms compared to the current standard dosing methods, and several available NSAIDs (ie, indomethacin, aceclofenac, ketoprofen, flurbiporfen, lornoxicam) have been very recently modified in their formulation, in order to obtain chronotherapeutical effects in RA.

Keywords: Corticosteroids; DMARDs (synthetic); Inflammation; NSAIDs; Rheumatoid Arthritis.

Figures

Figure 1
Figure 1
Circadian sequence of nocturnal hormone secretion that induces activation (melatonin, prolactin) and/or dowregulation (cortisol) of the immune inflammatory response during the night. Clinical consequences of altered hormonal balance in rheumatoid arthritis (RA) include morning symptoms such as joint stiffness and pain.
Figure 2
Figure 2
The daily neuroimmunoendocrine rhythms (gonadal, adrenal, pituitary hormones) are controlled by a central pacemaker, which is found in a hypothalamic region called the suprachiasmatic nucleus (SCN) of the central nervous system (CNS). APC, antigen presenting cell; DHEA, dehydroepiandrosterone; Th, T helper cell; Treg, regulatory T cell.
Figure 3
Figure 3
Basically, melatonin increases and cortisol reduces the immune/inflammatory reaction following a circadian rhythm. Reduced efficiency of the HPA axis activity related to chronic stimulation, such as in rheumatoid arthritis (RA), can induce a partial adrenal insufficiency. The consequence is reduced cortisol availability and reduced downregulation of the night immune/inflammatory response. HPA, hypothalamus-pituitary-adrenal axis.
Figure 4
Figure 4
Low-dose glucocorticoid chronotherapy in rheumatoid arthritis (RA) include the night-time-release prednisone, a timing drug release formulation with administration around 22–23 (22:00–23:00) and releasing prednisone around 2:00–3:00. Other therapeutical approaches used in RA, for example, with disease-modifying antirheumatic drugs (DMARDs: ie, methotrexate) and non-steroidal anti-inflammatory drugs (NSAIDs), should follow the same concept of glucocorticoid chronotherapy.

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