Circadian Use of Glucocorticoids in Rheumatoid Arthritis

Cutolo, Maurizio; Sulli, Alberto; Pincus, Theodore

doi:10.1159/000362733

Cited by 18 publications

(12 citation statements)

References 49 publications

(67 reference statements)

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“…All the investigations confirmed that the specific timing of exogenous prednisone availability, linked to the interaction between IL-6 and the HPA axis, may correct in RA a postulated deficiency regarding the HPA control [ 38 ].…”

Section: Low-dose Glucocorticoids and Chronotherapy In Rheumatoid Artmentioning

confidence: 81%

Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

Paolino¹,

Cutolo²,

Pizzorni³

2017

Reumatologia

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Morning symptoms of rheumatoid arthritis (RA) are linked to circadian increase of night inflammation, supported by inadequate cortisol secretion in active disease. Therefore, exogenous glucocorticoid administration in RA is recommended by EULAR and ACR from the beginning of the diagnosis, since may partially act like a “replacement therapy”. In addition, the prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective when exogenous glucocorticoid administration is managed with a night-time-release formulation.Despite a considerably higher cost than conventional prednisone (immediate release), chronotherapy with night-time-release prednisone has been recognized a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic disease-modifying antirheumatic drugs (DMARDs). Interestingly, since different cell populations involved in the inflammatory process are particularly activated during the night (i.e. monocytes, macrophages), other therapeutical approaches used in RA, such as conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs) should follow the same concepts of glucocorticoid chronotherapy. Therefore, bedtime methotrexate chronotherapy was found to better manage RA symptoms, and several available NSAIDs (i.e. indomethacin, aceclofenac, ketoprofen, flurbiprofen, lornoxicam) have been recently modified in their formulation, in order to obtain more focused night action.

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Section: Low-dose Glucocorticoids and Chronotherapy In Rheumatoid Artmentioning

confidence: 81%

Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

Paolino¹,

Cutolo²,

Pizzorni³

2017

Reumatologia

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“…The peak of inflammatory factor production occurs in association with low levels of cortisol. TNF-α and IL-6 production during active phases is consistent with reduction of night-time cortisol production [ 230 ]. Cortisol production is regulated by circadian rhythms that present an elevated morning level, but normalizes by the evening in MS patients [ 231 ].…”

Section: Circadian Rhythms In Msmentioning

confidence: 84%

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

Vallée

Lecarpentier²,

Guillevin

et al. 2018

IJMS

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Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

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“…A characteristic feature of RA is the change in disease activity over the day, measured by symptoms, and circulating markers of the inflammatory process such as IL-6 [31, 32]. Indeed, there have been attempts to add circadian logic to therapy, with modified release prednisolone tablets entering the clinic [33].…”

Section: Discussionmentioning

confidence: 99%

Rheumatoid arthritis reprograms circadian output pathways

et al. 2019

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ObjectiveWe applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA).MethodsWe recruited adults (age 16–80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA.ResultsRA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases.ConclusionRA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.Electronic supplementary materialThe online version of this article (10.1186/s13075-019-1825-y) contains supplementary material, which is available to authorized users.

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Circadian Use of Glucocorticoids in Rheumatoid Arthritis

Cited by 18 publications

References 49 publications

Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

Rheumatoid arthritis reprograms circadian output pathways

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